{"gene":"LARP1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2015,"finding":"LARP1 functions as a repressor of TOP mRNA translation downstream of mTORC1: it associates with mTORC1 via RAPTOR, binds the 5'TOP motif of TOP mRNAs in an mTORC1-dependent manner, and competes with eIF4G for TOP mRNA binding. siRNA knockdown of LARP1 attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation.","method":"Co-immunoprecipitation (LARP1-RAPTOR), RNA immunoprecipitation, competition binding assays, siRNA knockdown with translation readouts, pharmacological mTORC1 inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, RIP, competition assay, functional siRNA rescue), replicated across several conditions and inhibitors","pmids":["25940091"],"is_preprint":false},{"year":2014,"finding":"LARP1 associates with actively translating ribosomes via PABP, associates with mTORC1, and is required for global protein synthesis as well as cell growth and proliferation. It stimulates translation of mRNAs containing a 5'TOP motif.","method":"Quantitative proteomic cap-binding screen (m7G cap pulldown), co-immunoprecipitation, polysome profiling, siRNA knockdown with cell growth/proliferation readouts","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomics plus reciprocal Co-IP and functional validation, replicated findings with multiple orthogonal methods","pmids":["24532714"],"is_preprint":false},{"year":2017,"finding":"LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Non-phosphorylated LARP1 interacts with both 5' and 3'UTRs of ribosomal protein mRNAs and inhibits their translation. Phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5'UTRs and relieves translational inhibition. Phosphorylated LARP1 then scaffolds mTORC1 on 3'UTRs of translationally competent RP mRNAs to facilitate mTORC1-dependent translation initiation.","method":"In vitro kinase assays (direct substrate validation), deep sequencing of LARP1-bound mRNAs (iCLIP/PAR-CLIP), phospho-mutant analysis, polysome profiling","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay establishing direct substrate relationship, deep sequencing of bound mRNAs, phospho-mutant functional analysis, multiple orthogonal methods","pmids":["28650797"],"is_preprint":false},{"year":2017,"finding":"Crystal structures of the human LARP1 DM15 region in complex with a 5'TOP motif, cap analog (m7GTP), and capped cytidine (m7GpppC) show that LARP1 directly binds the m7G cap and adjacent 5'TOP motif. This binding effectively impedes access of eIF4E to the cap, preventing eIF4F assembly on TOP mRNAs.","method":"X-ray crystallography (2.6, 1.8, and 1.7 Å resolution structures), cap-binding competition assays, immunoprecipitation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structures with biochemical competition and IP validation, multiple orthogonal methods in one study","pmids":["28379136"],"is_preprint":false},{"year":2018,"finding":"The C-terminal half of LARP1 (containing the DM15 cap-binding domain and an adjacent regulatory region) is necessary and sufficient to control TOP mRNA translation. Purified LARP1 represses TOP mRNA translation in vitro through combined recognition of both the TOP sequence and cap structure.","method":"Domain deletion/truncation analysis in cells, in vitro translation repression assay with purified LARP1, binding affinity measurements","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of translational repression with purified protein plus domain mapping in cells, multiple orthogonal methods","pmids":["29244122"],"is_preprint":false},{"year":2021,"finding":"mTORC1 phosphorylates LARP1 in vitro and in vivo at 26 rapamycin-sensitive phospho-serine/threonine residues distributed in 7 clusters. Phosphorylation of a cluster of residues proximal to the DM15 cap-binding region is particularly rapamycin-sensitive and regulates both RNA-binding and translation inhibitory activities. The La module (LaMod) remains constitutively bound to PABP regardless of mTORC1 activation status, while the DM15 'pendular hook' engages the TOP mRNA 5'-end to repress translation only when mTORC1 is inhibited.","method":"In vitro mTORC1 kinase assay, quantitative phosphoproteomics (mass spectrometry), phospho-mutant functional analysis, RNA binding assays, rapamycin/torin1 treatment","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay, site-specific phospho-mapping by MS, phospho-mutant functional analysis, multiple orthogonal methods","pmids":["33398329"],"is_preprint":false},{"year":2019,"finding":"Molecular dynamics simulations, biophysical assays, and X-ray crystallography reveal the mechanism of DM15 binding to TOP transcripts: residues C-terminal to the m7G-binding site play important roles in cap recognition, and an unusually static pocket that recognizes the +1 cytosine characteristic of TOP transcripts drives binding specificity.","method":"X-ray crystallography, molecular dynamics simulations, biophysical binding assays (ITC/SPR)","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures complemented by MD simulations and biophysical assays in a single study","pmids":["31676287"],"is_preprint":false},{"year":2010,"finding":"Mammalian LARP1 is found in a complex with poly(A)-binding protein (PABP) and eukaryotic initiation factor 4E (eIF4E), and is associated with 60S and 80S ribosomal subunits. siRNA-mediated reduction of LARP1 inhibits global protein synthesis, causes mitotic arrest, and delays cell migration. LARP1 protein localizes to the leading edge of migrating cells and interacts with cytoskeletal components.","method":"Co-immunoprecipitation (LARP1-PABP-eIF4E complex), sucrose gradient sedimentation (ribosome association), siRNA knockdown, immunofluorescence localization, cell migration assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ribosome fractionation, functional siRNA knockdown with specific cellular readouts (mitotic arrest, migration), localization imaging","pmids":["20430826"],"is_preprint":false},{"year":2013,"finding":"LARP1 specifically recognizes the 3' termini of normal poly(A) tails (identified by proteomics of poly(A)-tail-associated proteins) and stabilizes multiple mRNAs carrying 5'TOP sequences.","method":"Proteomics-based identification of poly(A)-terminus-binding proteins, mRNA stability assays following LARP1 manipulation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteomics identification followed by functional mRNA stability assays, single lab","pmids":["23711370"],"is_preprint":false},{"year":2015,"finding":"LARP1 interacts with the 3'UTRs of BCL2 and BIK mRNAs, stabilizing BCL2 mRNA but destabilizing BIK mRNA, with the net effect of resisting apoptosis in ovarian cancer cells. LARP1 knockdown reduces cancer cell survival and chemotherapy resistance.","method":"RNA immunoprecipitation (RIP), mRNA stability assays, siRNA knockdown, xenograft tumor models, transcriptomic analysis cross-referenced against LARP1 interactome","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP validation of direct 3'UTR interaction, functional stability assays, in vivo xenograft, single lab","pmids":["26717985"],"is_preprint":false},{"year":2014,"finding":"LARP1 is complexed to ~3000 mRNAs enriched for cancer pathways. mTOR mRNA is a prominent member of the LARP1 interactome and is stabilized by LARP1. LARP1 promotes cell migration, invasion, and anchorage-independent growth.","method":"RNA immunoprecipitation followed by sequencing (RIP-seq), mRNA stability assays, siRNA knockdown with migration/invasion/anchorage-independent growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP-seq for target identification, functional mRNA stability and cellular assays, single lab","pmids":["25531318"],"is_preprint":false},{"year":2019,"finding":"The LARP1 La-Module (N-terminal region) binds TOP motifs in a cap-independent manner and also recognizes poly(A) RNA. The La-Module can simultaneously engage TOP motifs and poly(A) RNA, suggesting LARP1 can bridge both ends of TOP mRNAs.","method":"Electrophoretic mobility shift assays (EMSA), fluorescence polarization binding assays, in vitro RNA binding with purified La-Module","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays with purified protein, multiple RNA substrates tested, single lab","pmids":["31601159"],"is_preprint":false},{"year":2020,"finding":"LARP1 is established as the primary translation regulator of mRNAs with classical TOP motifs genome-wide. The DM15 cap-binding domain and TOP sequence features together determine regulatory potency. Analysis across 16 mammalian tissues reveals constitutive and tissue-specific sets of TOP mRNAs regulated by LARP1.","method":"Genome-wide ribosome profiling (Ribo-seq), LARP1 knockout/knockdown coupled with transcriptome-wide translation analysis, quantitative TOPscore metric development","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ribosome profiling in LARP1 KO/KD cells, transcriptome-scale analysis, multiple cell types and tissues, highly rigorous","pmids":["32094190"],"is_preprint":false},{"year":2020,"finding":"The isolated La-module of LARP1 mediates poly(A) length protection and mRNA stabilization in HEK293 cells, dependent on a PAM2 motif that binds PABP. A point mutation in the PAM2 motif impairs mRNA stabilization and PABP binding in vivo, but does not impair oligo(A) RNA binding by the purified recombinant La-module in vitro.","method":"In vivo mRNA stabilization assay, poly(A) length protection assay, co-immunoprecipitation, point mutagenesis of PAM2 motif, in vitro RNA binding with purified protein","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of specific PAM2 residue with both in vivo and in vitro functional consequences, multiple orthogonal methods","pmids":["33292040"],"is_preprint":false},{"year":2022,"finding":"Crystal structures of the LARP1 La motif (LaM) domain in complex with poly(A) RNA show the LaM alone (without an RRM) is sufficient for binding poly(A) RNA with submicromolar affinity and specificity, with highest specificity for the RNA 3'-end. Residues Q333, Y336, and F348 are critical for binding. LARP1 La-module binding has functional relevance for poly(A) 3' protection in cells.","method":"X-ray crystallography (multiple high-resolution structures with different RNA ligands), ITC binding measurements, mutagenesis of critical residues, quantitative mRNA stabilization assay, poly(A) tail-sequencing in cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures, mutagenesis of critical residues, functional validation in cells, multiple orthogonal methods in one study","pmids":["35979957"],"is_preprint":false},{"year":2022,"finding":"TOP mRNA translation positively correlates with poly(A) tail length under mTOR-active conditions. LARP1 is indispensable for mTOR-regulated poly(A) tail-length dynamics: under amino-acid-starved/mTOR-inactive conditions, LARP1 interacts with non-canonical poly(A) polymerases to induce post-transcriptional polyadenylation of TOP mRNA targets, leading to accumulation of long-tailed TOP mRNAs and accelerated ribosomal loading upon nutrient recovery.","method":"Poly(A) tail-length sequencing, polysome profiling, co-immunoprecipitation (LARP1 with poly(A) polymerases), LARP1 knockout/knockdown with poly(A) length readouts","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — poly(A) tail sequencing, Co-IP of LARP1 with poly(A) polymerases, functional KO, single lab","pmids":["36288708"],"is_preprint":false},{"year":2021,"finding":"LARP1 complexed with the 40S ribosomal subunit protects TOP mRNA regulon from ribophagy under mTOR inhibition, preserving the translatome capacity for ribosome biogenesis resumption when growth conditions return permissive.","method":"Ribosome fractionation, RNA sequencing of LARP1-40S complex-associated mRNAs, ribophagy assays, mTOR inhibition experiments","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome fractionation and sequencing, functional ribophagy assay, single lab","pmids":["34818049"],"is_preprint":false},{"year":2021,"finding":"PABPC1 is required for the association of LARP1 with its specific mRNA targets. Non-TOP-containing mRNAs bound by LARP1 are in a translationally-repressed state even under control conditions. mRNAs bound by both LARP1 and PABPC1 are translationally repressed.","method":"RNA-binding protein capture upon mTOR inhibition (RBP capture-seq), co-immunoprecipitation, PABPC1 depletion with LARP1 mRNA-binding readout, polysome profiling","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RBP capture-seq, functional PABPC1 depletion affecting LARP1-mRNA association, single lab","pmids":["33332560"],"is_preprint":false},{"year":2023,"finding":"LARP1 acts as a general decelerator of deadenylation specifically in the 30–60 nucleotide poly(A) length window by preferentially associating with short poly(A) tails. LARP1 depletion causes accelerated deadenylation in the 30–60 nt range and global reduction of mRNA abundance. LARP1 interferes with CCR4-NOT-mediated deadenylation in vitro by forming a ternary complex with PABP and poly(A).","method":"Poly(A) tail-length pulse-chase measurement, LARP1 knockdown with poly(A) length and mRNA abundance readouts, in vitro deadenylation assay with purified CCR4-NOT and LARP1","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of CCR4-NOT inhibition by LARP1-PABP-poly(A) ternary complex, poly(A) pulse-chase in cells, KD functional analysis","pmids":["36849640"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures reveal that a previously uncharacterized domain of LARP1 directly binds to and occludes the mRNA channel of the 40S ribosomal subunit. Increased availability of free ribosomal subunits promotes 60S joining at the same interface to form LARP1-80S complexes. Contrary to expectations, ribosome binding is NOT required for LARP1-mediated TOP repression or stabilization.","method":"Cryo-EM structural determination of LARP1-40S and LARP1-80S complexes, domain mutagenesis to disrupt ribosome binding, functional TOP mRNA repression and stability assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures with functional mutagenesis and negative result (ribosome binding not required for repression/stabilization) validated by independent assays","pmids":["39533057"],"is_preprint":false},{"year":2024,"finding":"4EBP1/2 has a dominant role in translational repression of both 5'TOP and canonical mRNAs during pharmacological mTOR inhibition, whereas LARP1 selectively protects 5'TOP mRNAs from degradation rather than primarily repressing their translation. Single-molecule translation site imaging shows this distinction in living cells.","method":"Single-molecule translation site imaging (SunTag reporter), transcriptome-wide mRNA half-life analysis, LARP1 and 4EBP1/2 knockouts/knockdowns","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — single-molecule live-cell imaging plus transcriptome-wide half-life analysis with genetic knockouts, multiple orthogonal methods","pmids":["38363833"],"is_preprint":false},{"year":2024,"finding":"eIF4A1 enhances LARP1-mediated translational repression of TOP mRNAs during mTORC1 inhibition. eIF4A1 preferentially binds TOP mRNAs in a LARP1-dependent manner and increases the interaction between TOP mRNAs and LARP1, thereby strengthening translational repression upon mTORC1 inhibition.","method":"RNA pulldown followed by sequencing, ribosome profiling, co-immunoprecipitation, EIF4A1 deletion analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA pulldown-seq, ribosome profiling in EIF4A1 KO cells, Co-IP showing increased LARP1-TOP mRNA interaction, multiple orthogonal methods","pmids":["38773334"],"is_preprint":false},{"year":2022,"finding":"GCN2, a second nutrient-sensing kinase, converges on LARP1 to control TOP mRNA translation via two mechanisms: (1) ATF4-dependent transcriptional induction of LARP1 mRNA, and (2) GCN1-mediated recruitment of LARP1 to stalled ribosomes (GCN1 participates in a complex with LARP1 on stalled ribosomes).","method":"ChIP-seq (ATF4 binding at LARP1 locus), GCN2 knockout MEFs, co-immunoprecipitation (GCN1-LARP1 on stalled ribosomes), TOP mRNA translation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq for ATF4 target identification, Co-IP for GCN1-LARP1 complex, functional GCN2 KO, single lab","pmids":["35863436"],"is_preprint":false},{"year":2009,"finding":"Drosophila Larp exists in a physical complex with and genetically interacts with the translation regulator poly(A)-binding protein (PABP). Larp mutant-derived syncytial embryos show mitotic phenotypes including centrosome migration failure, centrosome detachment from spindle poles, multipolar spindle arrays, and cytokinetic defects. larp mutant males show meiotic defects similar to hypomorphic pAbp alleles.","method":"Co-immunoprecipitation (Larp-PABP complex), genetic epistasis (larp and pAbp double mutants), immunofluorescence (mitotic phenotype analysis)","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic epistasis and cellular phenotype analysis, Drosophila ortholog study","pmids":["19631203"],"is_preprint":false},{"year":2008,"finding":"C. elegans LARP-1 localizes to germline P bodies, attenuates Ras-MAPK signaling during oogenesis, and larp-1 null mutants have higher than normal levels of selected Ras-MAPK pathway mRNAs and proteins. larp-1 null oogenesis defects are suppressed or enhanced by down- or up-regulating Ras-MAPK pathway. LARP-1 binds RNA in vitro via both its La motif and LARP1 domain.","method":"In vitro RNA binding assays (La motif and LARP1 domain), genetic epistasis (larp-1 with Ras-MAPK pathway components), immunofluorescence (P body colocalization), mRNA/protein level analysis in larp-1 nulls","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro RNA binding, genetic epistasis, localization imaging, C. elegans ortholog study","pmids":["18515547"],"is_preprint":false},{"year":2010,"finding":"C. elegans LARP-1 promotes oogenesis by repressing fem-3 mRNA. Simultaneous depletion of larp-1 and nos-3 causes germline masculinization dependent on fem-3 activity. fem-3 mRNA levels are increased in larp-1 mutants, indicating LARP-1 suppresses fem-3 expression through a distinct mechanism from NOS-3.","method":"RNAi depletion, genetic epistasis (larp-1;nos-3 double knockdown with fem-3 activity requirement), qPCR/Western blot for TRA-1 and FEM protein levels","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined pathway placement, mRNA level analysis, C. elegans ortholog","pmids":["20663921"],"is_preprint":false},{"year":2021,"finding":"LARP1 and LARP4 share direct binding to poly(A) and to cytoplasmic PABP (PABPC1) through PAM2 motifs interacting with the MLLE domain of PABP. LARP1 can protect mRNA from deadenylation in a PAM2-dependent manner. The La-module of LARP1 interacts with PABP to stabilize poly(A) tails.","method":"Biochemical binding assays (PAM2-MLLE interaction), mRNA stabilization assays, co-immunoprecipitation","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — review synthesizing multiple experimental findings from the lab, supported by primary data from related papers, moderate confidence as a review","pmids":["33522422"],"is_preprint":false},{"year":2023,"finding":"O-GlcNAcylation of LARP1 at Ser672 by O-GlcNAc transferase (OGT) strengthens its binding to circCLNS1A and protects LARP1 from TRIM-25-mediated ubiquitination and proteolysis. LARP1 upregulation leads to DKK4 mRNA stabilization by competitively interacting with PABPC1 to prevent DKK4 mRNA from BTG2-dependent deadenylation and degradation.","method":"Co-immunoprecipitation (LARP1-circCLNS1A, LARP1-PABPC1), site-specific mutagenesis (Ser672), protein stability assays, RIP, RNA pull-down, mRNA stability assays, poly(A)-tail length assays","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — site-specific PTM mutagenesis, Co-IP, RIP, multiple orthogonal methods, single lab","pmids":["37070251"],"is_preprint":false},{"year":2025,"finding":"LARP1 interacts with the 5'UTR of EV-D68 RNA through its LAM domain, and this interaction is crucial for its antiviral function. EV-D68 protease 3Cpro cleaves LARP1 and PABPC1 to counteract LARP1-mediated inhibition of viral translation. Overexpression of LARP1 significantly inhibits EV-D68 replication. mTOR and CDK1 signaling pathways regulate LARP1's binding to viral RNA.","method":"Domain mapping (LAM domain interaction with viral 5'UTR), overexpression and siRNA knockdown with viral replication readouts, protease cleavage assays, mTOR/CDK1 pathway inhibitor experiments","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level mapping of viral RNA binding, functional overexpression/KD, protease cleavage mechanism, single lab","pmids":["40294010"],"is_preprint":false},{"year":2024,"finding":"The LARP1 PAM2 motif adopts a non-canonical single turn α-helix conformation for MLLE domain binding. Phenylalanine 496 in the PAM2 motif is essential for MLLE binding. NMR chemical shift perturbations defined the MLLE-binding segment within LARP1.","method":"NMR spectroscopy (chemical shift perturbation, heteronuclear NOE), isothermal titration calorimetry (ITC), PAM2 mutagenesis, AlphaFold3 modeling","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — NMR and ITC with mutagenesis, single lab, structural characterization of interaction","pmids":["41762867"],"is_preprint":false},{"year":2024,"finding":"The LARP1 LaM domain shows preferential binding to poly(A) sequences with single guanine substitutions over unmodified poly(A). Crystal structures of the LARP1 LaM with six different RNA ligands, including singly guanylated sequences, define the structural basis for this selectivity.","method":"X-ray crystallography (multiple structures), isothermal titration calorimetry (ITC)","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structures and ITC binding measurements, single lab, single study","pmids":["39016322"],"is_preprint":false},{"year":2025,"finding":"Brain-specific knockout of Larp1 in mice significantly decreases brain mass, reduces neuronal density, depletes TOP mRNA levels by more than 50%, and selectively removes TOP mRNAs from synapses. Larp1-deficient mice are severely impaired in spatial learning and memory.","method":"Brain-specific conditional knockout (Cre-lox), brain mass and neuron density quantification, RNA-seq (TOP mRNA abundance), synaptic fractionation with RNA-seq, behavioral testing (spatial memory)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific CNS phenotypes and molecular readouts, preprint (not yet peer-reviewed)","pmids":["41278816"],"is_preprint":true},{"year":2026,"finding":"LARP1's ribosome-binding region is part of a previously unrecognized RNA recognition motif (RRM) domain that directly interacts with its TOP-binding HEAT repeat (DM15) domain. Ribosome binding is both sufficient in vitro and required in cells for LARP1 to bind, repress, and stabilize TOP mRNAs via unfolding and remodeling of the RRM domain. RRM mutations that disrupt ribosome binding constitutively repress TOPs and compromise cell fitness.","method":"Cryo-EM (structural identification of RRM), in vitro ribosome binding assay, RRM mutagenesis, TOP mRNA repression and stability assays in cells, cell fitness/growth assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — cryo-EM structure, in vitro reconstitution, mutagenesis with functional readouts, preprint (not yet peer-reviewed)","pmids":["42039457"],"is_preprint":true},{"year":2025,"finding":"5'TOP motifs are sufficient to increase mRNA targeting to lysosomes for degradation in a LARP1-dependent manner, establishing a role for LARP1 in selective lysosomal delivery of TOP mRNAs.","method":"Lysosomal RNA profiling, LARP1 depletion with lysosomal TOP mRNA accumulation readout, reporter assays with TOP motif","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — single preprint, LARP1-dependence shown by depletion but molecular mechanism not fully elaborated in abstract","pmids":["bio_10.1101_2025.09.09.674968"],"is_preprint":true},{"year":2025,"finding":"LARP1 overexpression alleviates angiotensin II-induced cardiac remodeling. LARP1 binds ATP2A2 (SERCA2a) mRNA and enhances its stability; ATP2A2 overexpression reverses hypertrophic and fibrotic changes in LARP1-deficient cardiomyocytes.","method":"RNA immunoprecipitation (RIP), RNA pull-down, mRNA stability assay (actinomycin D), AAV9-LARP1 overexpression in vivo, LARP1 KO mice with cardiac phenotype readouts","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, RNA pull-down confirming direct LARP1-ATP2A2 mRNA binding, in vivo KO and overexpression with specific molecular rescue, single lab","pmids":["41126333"],"is_preprint":false},{"year":2022,"finding":"LARP1 positively modulates MYC expression by associating with the MYC 3'UTR. Antisense oligonucleotide-mediated blocking of the LARP1–MYC 3'UTR interaction reduces MYC expression. MYC reciprocally modulates LARP1 expression by targeting its enhancer, establishing a positive feedback loop. IGF2BP3 and YBX1 are identified as LARP1-interacting proteins.","method":"RIP-seq (LARP1 interactome), antisense oligonucleotide blocking assay, co-immunoprecipitation (LARP1-IGF2BP3, LARP1-YBX1), ChIP (MYC at LARP1 enhancer), mRNA stability/translation assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP-seq, ASO blocking, Co-IP, ChIP, single lab, multiple orthogonal methods","pmids":["35195778"],"is_preprint":false}],"current_model":"LARP1 is an mTORC1-regulated RNA-binding protein that acts as a phosphorylation-sensitive molecular switch for translational control of 5'TOP mRNAs (encoding ribosomal proteins and translation factors): when mTORC1 is inactive, unphosphorylated LARP1 directly binds the m7G cap and adjacent 5'TOP motif via its C-terminal DM15 domain (structural mechanism established by X-ray crystallography), blocking eIF4F assembly; when mTORC1 is active, site-specific phosphorylation of LARP1 (including by Akt/S6K1) releases its repressive 5'-end engagement while its N-terminal La-module simultaneously binds poly(A) tails via a PAM2-PABP interaction to protect mRNAs from CCR4-NOT-mediated deadenylation; additionally, a newly identified RRM domain mediates direct binding to non-translating ribosomal subunits and is required for LARP1 to engage and repress TOP mRNAs, positioning LARP1 as a ribosome-sensing coordinator that couples free ribosome availability to ribosomal protein synthesis."},"narrative":{"mechanistic_narrative":"LARP1 is an mTORC1-regulated, phosphorylation-sensitive RNA-binding protein that serves as the principal post-transcriptional controller of 5'TOP mRNAs encoding ribosomal proteins and translation factors [PMID:25940091, PMID:28650797, PMID:32094190]. It operates as a bipartite molecular switch: its C-terminal DM15 (HEAT-repeat) domain directly engages both the m7G cap and the adjacent 5'TOP motif, sterically blocking eIF4E/eIF4F assembly and repressing translation when mTORC1 is inactive, with binding specificity driven by an invariant pocket that reads the +1 cytidine characteristic of TOP transcripts [PMID:28379136, PMID:31676287, PMID:29244122]. mTORC1 (and Akt/S6K1) directly phosphorylate LARP1 at multiple clustered serine/threonine residues, and phosphorylation near the DM15 region dissociates LARP1 from the 5'-end to relieve repression [PMID:28650797, PMID:33398329]. In parallel, its N-terminal La-module — through a La-motif that binds poly(A) 3'-ends and a PAM2 motif that docks onto the MLLE domain of cytoplasmic PABP — protects poly(A) tails and stabilizes TOP mRNAs, decelerating CCR4-NOT-mediated deadenylation by forming a LARP1–PABP–poly(A) ternary complex [PMID:33398329, PMID:33292040, PMID:35979957, PMID:36849640, PMID:41762867]. Beyond translational repression per se, live-cell and transcriptome analyses establish that under mTOR inhibition LARP1's dominant function is selective protection of 5'TOP mRNAs from degradation, preserving the TOP regulon for rapid recovery, while a newly defined RRM domain couples LARP1 to non-translating 40S/80S ribosomal subunits to license TOP engagement [PMID:38363833, PMID:39533057, PMID:42039457]. LARP1 broadly stabilizes and tunes specific transcripts in cancer and tissue contexts — including BCL2/BIK, mTOR, MYC, and SERCA2a (ATP2A2) mRNAs — linking it to apoptosis resistance, proliferation, and cardiac remodeling [PMID:26717985, PMID:25531318, PMID:35195778, PMID:41126333], and brain-specific loss depletes synaptic TOP mRNAs and impairs spatial memory [PMID:41278816].","teleology":[{"year":2008,"claim":"Established LARP1 orthologs as RNA-binding, PABP-associated post-transcriptional regulators with conserved developmental roles, framing the protein family before its mammalian translational function was known.","evidence":"C. elegans larp-1 genetics, in vitro RNA binding via La motif and LARP1 domain, P-body localization; Drosophila Larp-PABP Co-IP and mitotic/meiotic phenotypes","pmids":["18515547","20663921","19631203"],"confidence":"Medium","gaps":["Direct molecular targets in mammals not yet defined","TOP mRNA connection not yet made","ortholog phenotypes not mechanistically linked to translation"]},{"year":2010,"claim":"Placed mammalian LARP1 physically within the translation apparatus and showed it is required for global protein synthesis, defining it as a translation-associated factor rather than a generic RNA-binding protein.","evidence":"Co-IP of LARP1-PABP-eIF4E complex, sucrose-gradient ribosome association (60S/80S), siRNA knockdown with mitotic arrest and migration defects","pmids":["20430826"],"confidence":"High","gaps":["Specific mRNA targets not identified","no mechanism for how LARP1 acts on ribosomes","directness of eIF4E association unresolved"]},{"year":2014,"claim":"Identified the transcriptome-scale LARP1 interactome and linked LARP1 to 5'TOP mRNAs and mTORC1, establishing it as a specific regulator of the TOP regulon and cancer-relevant transcripts.","evidence":"Cap-binding proteomic screen, RIP-seq (~3000 mRNAs), polysome profiling, mTORC1 Co-IP, functional siRNA with growth/invasion readouts","pmids":["24532714","25531318"],"confidence":"High","gaps":["Whether LARP1 activates or represses TOP translation was initially ambiguous","no structural basis for RNA recognition","phosphoregulation not yet shown"]},{"year":2015,"claim":"Resolved LARP1 as an mTORC1-dependent repressor that competes with eIF4G for TOP mRNAs, and extended its target stabilization to apoptosis-regulating mRNAs in cancer.","evidence":"LARP1-RAPTOR Co-IP, mTORC1-dependent RIP, eIF4G competition assay, siRNA rescue of rapamycin/Torin1 effects; RIP and stability assays for BCL2/BIK in ovarian cancer with xenografts","pmids":["25940091","26717985"],"confidence":"High","gaps":["Phosphorylation sites mediating mTORC1 control not mapped","no atomic-resolution view of cap/TOP recognition","reconciliation of repressor vs stabilizer roles incomplete"]},{"year":2017,"claim":"Defined LARP1 as a direct mTORC1/Akt-S6K1 substrate whose phosphorylation acts as the switch between repression and translation-competence, providing the kinase logic of the system.","evidence":"In vitro kinase assays, iCLIP/PAR-CLIP of LARP1-bound 5' and 3'UTRs, phospho-mutant analysis, polysome profiling","pmids":["28650797"],"confidence":"High","gaps":["Functional role of each phospho-cluster not separated","scaffolding model for mTORC1 on 3'UTRs needs structural support"]},{"year":2018,"claim":"Established the structural and biochemical basis for cap-dependent TOP repression: the DM15 domain binds m7G cap and the adjacent TOP motif to occlude eIF4E, and the C-terminal half is sufficient to repress in vitro.","evidence":"X-ray structures of DM15 with m7GTP, m7GpppC and TOP motif; cap-binding competition; purified-LARP1 in vitro repression and domain truncation","pmids":["28379136","29244122","31676287"],"confidence":"High","gaps":["Mechanism of phospho-release at the structural level not captured","role of N-terminal La-module in repression not yet integrated"]},{"year":2020,"claim":"Bisected the LARP1 mechanism into a constitutive PABP-bound La-module and a regulated DM15 'pendular hook', and demonstrated genome-wide that LARP1 is the primary TOP-mRNA translation regulator.","evidence":"mTORC1 phosphoproteomics (26 sites/7 clusters), phospho-mutant RNA-binding assays; La-module EMSA/FP binding to TOP and poly(A); PAM2 mutagenesis with in vivo poly(A) protection; Ribo-seq in LARP1 KO across 16 tissues (TOPscore)","pmids":["33398329","31601159","33292040","32094190"],"confidence":"High","gaps":["In vitro vs in vivo discrepancy in La-module RNA binding (PAM2 mutant)","how phospho-clusters quantitatively tune affinity unresolved"]},{"year":2021,"claim":"Showed PABPC1 dependence of LARP1 target selection and a role for LARP1-40S complexes in protecting the TOP regulon from ribophagy, broadening LARP1 from translational control toward mRNA preservation under stress.","evidence":"RBP capture-seq with PABPC1 depletion, Co-IP, polysome profiling; ribosome fractionation, RNA-seq of LARP1-40S complexes, ribophagy assays under mTOR inhibition","pmids":["33332560","34818049"],"confidence":"Medium","gaps":["Single-lab findings","direct ribosome-binding interface not defined here","mechanism coupling 40S to ribophagy protection unresolved"]},{"year":2022,"claim":"Provided crystallographic proof that the LaM domain alone binds poly(A) 3'-ends with submicromolar specificity and uncovered LARP1's control of TOP poly(A) dynamics, plus a GCN2/ATF4 input that converges on LARP1.","evidence":"LaM-poly(A) crystal structures with mutagenesis and cellular poly(A) protection; poly(A) tail-seq with non-canonical poly(A) polymerase Co-IP; GCN2 KO MEFs, ATF4 ChIP-seq, GCN1-LARP1 Co-IP on stalled ribosomes; MYC 3'UTR feedback loop with IGF2BP3/YBX1 interactors","pmids":["35979957","36288708","35863436","35195778"],"confidence":"Medium","gaps":["Identity of non-canonical poly(A) polymerases partnering LARP1 not fully defined","GCN1-LARP1 recruitment mechanism single-lab","MYC feedback loop generality unknown"]},{"year":2023,"claim":"Reconstituted LARP1 as a sequence-window-specific decelerator of deadenylation, showing it forms a ternary complex with PABP and poly(A) to antagonize CCR4-NOT and broadly stabilize mRNAs.","evidence":"Poly(A) pulse-chase in cells, LARP1 KD with poly(A) and abundance readouts, in vitro deadenylation with purified CCR4-NOT and LARP1; O-GlcNAc/TRIM25 PTM control of LARP1 stability with DKK4 mRNA stabilization","pmids":["36849640","37070251"],"confidence":"High","gaps":["Why LARP1 acts preferentially in the 30-60 nt window mechanistically unclear","PTM regulation single-lab and context-specific"]},{"year":2024,"claim":"Refined the division of labor in mTOR-inhibited cells (4EBP1/2 represses translation, LARP1 protects TOP mRNAs from degradation), identified the LARP1-40S/80S ribosome interface by cryo-EM, and added eIF4A1 and PAM2-MLLE structural detail.","evidence":"Single-molecule SunTag imaging with half-life analysis and KOs; cryo-EM of LARP1-40S/80S with mRNA-channel occlusion and ribosome-binding mutants; eIF4A1 RNA pulldown-seq and Ribo-seq; NMR/ITC of non-canonical PAM2 helix (F496); LaM crystal structures with guanylated poly(A)","pmids":["38363833","39533057","38773334","41762867","39016322"],"confidence":"High","gaps":["Cryo-EM study found ribosome binding NOT required for repression/stabilization, conflicting with later RRM model","physiological role of guanine-tolerant poly(A) recognition unclear"]},{"year":2025,"claim":"Extended LARP1 function to physiology and disease: brain-specific loss depletes synaptic TOP mRNAs and impairs memory; LARP1 stabilizes SERCA2a mRNA to limit cardiac remodeling; and it acts as an antiviral factor cleaved by EV-D68 protease.","evidence":"Brain-specific Larp1 cKO mice with RNA-seq, synaptic fractionation and behavior (preprint); LARP1 KO/AAV9 overexpression with ATP2A2 RIP/pull-down rescue in heart; EV-D68 5'UTR-LAM domain mapping with overexpression/KD and 3Cpro cleavage assays","pmids":["41278816","41126333","40294010"],"confidence":"Medium","gaps":["Brain study is a preprint","tissue-specific target selectivity mechanisms not defined","antiviral specificity across enteroviruses untested"]},{"year":2026,"claim":"Identified the LARP1 ribosome-binding region as an RRM domain that intramolecularly engages DM15, proposing that ribosome sensing via RRM remodeling licenses TOP binding, repression and stabilization.","evidence":"Cryo-EM identification of RRM, in vitro ribosome-binding reconstitution, RRM mutagenesis with TOP repression/stability and cell-fitness readouts (preprint)","pmids":["42039457"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","directly conflicts with prior finding that ribosome binding is not required for repression/stabilization","in vivo relevance of RRM-DM15 interplay untested"]},{"year":null,"claim":"It remains unresolved how the structurally defined inputs (phospho-clusters, RRM-ribosome sensing, eIF4A1, PABP) are quantitatively integrated to set the repression-vs-protection balance for individual TOP and non-TOP transcripts across tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["Conflicting evidence on whether ribosome binding is required for TOP regulation","no unified model linking phosphostate to differential target fate","lysosomal TOP-mRNA delivery role rests on a single low-confidence preprint"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3,11,14,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,12,20]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,2,4,12]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,1]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[7,16,19]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,18,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,4,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5]}],"complexes":["LARP1-PABP-eIF4E cap-binding complex","LARP1-40S/80S ribosome complex","LARP1-PABP-poly(A) ternary complex (anti-CCR4-NOT)"],"partners":["PABPC1","RAPTOR","EIF4E","EIF4A1","GCN1","IGF2BP3","YBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PKG0","full_name":"La-related protein 1","aliases":["La ribonucleoprotein domain family member 1"],"length_aa":1096,"mass_kda":123.5,"function":"RNA-binding protein that regulates the translation of specific target mRNA species downstream of the mTORC1 complex, in function of growth signals and nutrient availability (PubMed:20430826, PubMed:23711370, PubMed:24532714, PubMed:25940091, PubMed:28650797, PubMed:28673543, PubMed:29244122). Interacts on the one hand with the 3' poly-A tails that are present in all mRNA molecules, and on the other hand with the 7-methylguanosine cap structure of mRNAs containing a 5' terminal oligopyrimidine (5'TOP) motif, which is present in mRNAs encoding ribosomal proteins and several components of the translation machinery (PubMed:23711370, PubMed:25940091, PubMed:26206669, PubMed:28379136, PubMed:28650797, PubMed:29244122). The interaction with the 5' end of mRNAs containing a 5'TOP motif leads to translational repression by preventing the binding of EIF4G1 (PubMed:25940091, PubMed:28379136, PubMed:28650797, PubMed:29244122). When mTORC1 is activated, LARP1 is phosphorylated and dissociates from the 5' untranslated region (UTR) of mRNA (PubMed:25940091, PubMed:28650797). Does not prevent binding of EIF4G1 to mRNAs that lack a 5'TOP motif (PubMed:28379136). Interacts with the free 40S ribosome subunit and with ribosomes, both monosomes and polysomes (PubMed:20430826, PubMed:24532714, PubMed:25940091, PubMed:28673543). Under normal nutrient availability, interacts primarily with the 3' untranslated region (UTR) of mRNAs encoding ribosomal proteins and increases protein synthesis (PubMed:23711370, PubMed:28650797). Associates with actively translating ribosomes and stimulates translation of mRNAs containing a 5'TOP motif, thereby regulating protein synthesis, and as a consequence, cell growth and proliferation (PubMed:20430826, PubMed:24532714). Stabilizes mRNAs species with a 5'TOP motif, which is required to prevent apoptosis (PubMed:20430826, PubMed:23711370, PubMed:25940091, PubMed:28673543) (Microbial infection) Positively regulates the replication of dengue virus (DENV)","subcellular_location":"Cytoplasm; Cytoplasmic granule","url":"https://www.uniprot.org/uniprotkb/Q6PKG0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LARP1","classification":"Not Classified","n_dependent_lines":241,"n_total_lines":1208,"dependency_fraction":0.19950331125827814},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTCF","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"EIF2S3","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LARP1","total_profiled":1310},"omim":[{"mim_id":"620467","title":"La RIBONUCLEOPROTEIN 1B; LARP1B","url":"https://www.omim.org/entry/620467"},{"mim_id":"616808","title":"SHIFTLESS ANTIVIRAL INHIBITOR OF RIBOSOMAL FRAMESHIFTING; SHFL","url":"https://www.omim.org/entry/616808"},{"mim_id":"616513","title":"La RIBONUCLEOPROTEIN 4B; LARP4B","url":"https://www.omim.org/entry/616513"},{"mim_id":"612059","title":"La RIBONUCLEOPROTEIN 1, TRANSLATIONAL REGULATOR; LARP1","url":"https://www.omim.org/entry/612059"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LARP1"},"hgnc":{"alias_symbol":["LARP","KIAA0731","MGC19556","Lar1","Lhp1"],"prev_symbol":[]},"alphafold":{"accession":"Q6PKG0","domains":[{"cath_id":"1.10.10.10","chopping":"401-486","consensus_level":"high","plddt":89.0473,"start":401,"end":486},{"cath_id":"1.25.40","chopping":"876-1027","consensus_level":"medium","plddt":91.1071,"start":876,"end":1027}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PKG0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PKG0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PKG0-F1-predicted_aligned_error_v6.png","plddt_mean":53.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LARP1","jax_strain_url":"https://www.jax.org/strain/search?query=LARP1"},"sequence":{"accession":"Q6PKG0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PKG0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PKG0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PKG0"}},"corpus_meta":[{"pmid":"25940091","id":"PMC_25940091","title":"La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1).","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25940091","citation_count":215,"is_preprint":false},{"pmid":"24532714","id":"PMC_24532714","title":"Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5'TOP mRNA translation.","date":"2014","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/24532714","citation_count":210,"is_preprint":false},{"pmid":"28650797","id":"PMC_28650797","title":"LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28650797","citation_count":173,"is_preprint":false},{"pmid":"28379136","id":"PMC_28379136","title":"La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28379136","citation_count":152,"is_preprint":false},{"pmid":"32094190","id":"PMC_32094190","title":"Global analysis of LARP1 translation targets reveals tunable and dynamic features of 5' TOP motifs.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32094190","citation_count":134,"is_preprint":false},{"pmid":"26717985","id":"PMC_26717985","title":"The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26717985","citation_count":133,"is_preprint":false},{"pmid":"24332370","id":"PMC_24332370","title":"XRN4 and LARP1 are required for a heat-triggered mRNA decay pathway involved in plant acclimation and survival during thermal stress.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24332370","citation_count":125,"is_preprint":false},{"pmid":"25531318","id":"PMC_25531318","title":"LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25531318","citation_count":124,"is_preprint":false},{"pmid":"20430826","id":"PMC_20430826","title":"The RNA binding protein Larp1 regulates cell division, apoptosis and cell migration.","date":"2010","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/20430826","citation_count":103,"is_preprint":false},{"pmid":"29244122","id":"PMC_29244122","title":"La-related protein 1 (LARP1) repression of TOP mRNA translation is mediated through its cap-binding domain and controlled by an adjacent regulatory region.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29244122","citation_count":102,"is_preprint":false},{"pmid":"23711370","id":"PMC_23711370","title":"LARP1 specifically recognizes the 3' terminus of poly(A) mRNA.","date":"2013","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23711370","citation_count":91,"is_preprint":false},{"pmid":"29969631","id":"PMC_29969631","title":"CircRNA circ-BANP-mediated miR-503/LARP1 signaling contributes to lung cancer progression.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29969631","citation_count":83,"is_preprint":false},{"pmid":"19631203","id":"PMC_19631203","title":"Drosophila Larp associates with poly(A)-binding protein and is required for male fertility and syncytial embryo development.","date":"2009","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19631203","citation_count":81,"is_preprint":false},{"pmid":"33398329","id":"PMC_33398329","title":"mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33398329","citation_count":81,"is_preprint":false},{"pmid":"33054972","id":"PMC_33054972","title":"Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33054972","citation_count":77,"is_preprint":false},{"pmid":"32233986","id":"PMC_32233986","title":"Controversies around the function of LARP1.","date":"2020","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/32233986","citation_count":65,"is_preprint":false},{"pmid":"18515547","id":"PMC_18515547","title":"C. elegans La-related protein, LARP-1, localizes to germline P bodies and attenuates Ras-MAPK signaling during oogenesis.","date":"2008","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18515547","citation_count":64,"is_preprint":false},{"pmid":"29722158","id":"PMC_29722158","title":"LARP1 on TOP of ribosome production.","date":"2018","source":"Wiley interdisciplinary reviews. RNA","url":"https://pubmed.ncbi.nlm.nih.gov/29722158","citation_count":59,"is_preprint":false},{"pmid":"21304947","id":"PMC_21304947","title":"Control of flowering and cell fate by LIF2, an RNA binding partner of the polycomb complex component LHP1.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21304947","citation_count":54,"is_preprint":false},{"pmid":"16972870","id":"PMC_16972870","title":"DamID, a new tool for studying plant chromatin profiling in vivo, and its use to identify putative LHP1 target loci.","date":"2006","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16972870","citation_count":42,"is_preprint":false},{"pmid":"29039571","id":"PMC_29039571","title":"LARP1 is regulated by the XIST/miR-374a axis and functions as an oncogene in non-small cell lung carcinoma.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/29039571","citation_count":39,"is_preprint":false},{"pmid":"33347535","id":"PMC_33347535","title":"Hsa_circRNA_002144 promotes growth and metastasis of colorectal cancer through regulating miR-615-5p/LARP1/mTOR pathway.","date":"2021","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/33347535","citation_count":39,"is_preprint":false},{"pmid":"21251106","id":"PMC_21251106","title":"TFL2/LHP1 is involved in auxin biosynthesis through positive regulation of YUCCA genes.","date":"2011","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21251106","citation_count":39,"is_preprint":false},{"pmid":"17951964","id":"PMC_17951964","title":"A Drosophila orthologue of larp protein family is required for multiple processes in male meiosis.","date":"2007","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/17951964","citation_count":37,"is_preprint":false},{"pmid":"25892282","id":"PMC_25892282","title":"The role of LARP1 in translation and beyond.","date":"2015","source":"Wiley interdisciplinary reviews. RNA","url":"https://pubmed.ncbi.nlm.nih.gov/25892282","citation_count":35,"is_preprint":false},{"pmid":"38363833","id":"PMC_38363833","title":"Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5'TOP mRNAs.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38363833","citation_count":33,"is_preprint":false},{"pmid":"33522422","id":"PMC_33522422","title":"LARP1 and LARP4: up close with PABP for mRNA 3' poly(A) protection and stabilization.","date":"2021","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/33522422","citation_count":33,"is_preprint":false},{"pmid":"31601159","id":"PMC_31601159","title":"The LARP1 La-Module recognizes both ends of TOP mRNAs.","date":"2019","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/31601159","citation_count":33,"is_preprint":false},{"pmid":"33332560","id":"PMC_33332560","title":"The mTOR regulated RNA-binding protein LARP1 requires PABPC1 for guided mRNA interaction.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33332560","citation_count":32,"is_preprint":false},{"pmid":"29212661","id":"PMC_29212661","title":"Disruption of an RNA-binding hinge region abolishes LHP1-mediated epigenetic repression.","date":"2017","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/29212661","citation_count":32,"is_preprint":false},{"pmid":"31676287","id":"PMC_31676287","title":"Capturing the Mechanism Underlying TOP mRNA Binding to LARP1.","date":"2019","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/31676287","citation_count":31,"is_preprint":false},{"pmid":"33292040","id":"PMC_33292040","title":"The isolated La-module of LARP1 mediates 3' poly(A) protection and mRNA stabilization, dependent on its intrinsic PAM2 binding to PABPC1.","date":"2020","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/33292040","citation_count":30,"is_preprint":false},{"pmid":"34818049","id":"PMC_34818049","title":"The 40S-LARP1 complex reprograms the cellular translatome upon mTOR inhibition to preserve the protein synthetic capacity.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34818049","citation_count":30,"is_preprint":false},{"pmid":"35979957","id":"PMC_35979957","title":"Structural basis of 3'-end poly(A) RNA recognition by LARP1.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/35979957","citation_count":29,"is_preprint":false},{"pmid":"36288708","id":"PMC_36288708","title":"mTOR- and LARP1-dependent regulation of TOP mRNA poly(A) tail and ribosome loading.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36288708","citation_count":29,"is_preprint":false},{"pmid":"36849640","id":"PMC_36849640","title":"Short poly(A) tails are protected from deadenylation by the LARP1-PABP complex.","date":"2023","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36849640","citation_count":28,"is_preprint":false},{"pmid":"29234344","id":"PMC_29234344","title":"LHP1 Could Act as an Activator and a Repressor of Transcription in Plants.","date":"2017","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/29234344","citation_count":25,"is_preprint":false},{"pmid":"29793052","id":"PMC_29793052","title":"LHP1 Interacts with ATRX through Plant-Specific Domains at Specific Loci Targeted by PRC2.","date":"2018","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/29793052","citation_count":24,"is_preprint":false},{"pmid":"39533057","id":"PMC_39533057","title":"LARP1 binds ribosomes and TOP mRNAs in repressed complexes.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/39533057","citation_count":22,"is_preprint":false},{"pmid":"33742112","id":"PMC_33742112","title":"GmBTB/POZ promotes the ubiquitination and degradation of LHP1 to regulate the response of soybean to Phytophthora sojae.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33742112","citation_count":18,"is_preprint":false},{"pmid":"32286153","id":"PMC_32286153","title":"LARP1 isoform expression in human cancer cell lines.","date":"2020","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/32286153","citation_count":16,"is_preprint":false},{"pmid":"20663921","id":"PMC_20663921","title":"LARP-1 promotes oogenesis by repressing fem-3 in the C. elegans germline.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/20663921","citation_count":16,"is_preprint":false},{"pmid":"33680937","id":"PMC_33680937","title":"Downregulation of the lncRNA ASB16-AS1 Decreases LARP1 Expression and Promotes Clear Cell Renal Cell Carcinoma Progression via miR-185-5p/miR-214-3p.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33680937","citation_count":13,"is_preprint":false},{"pmid":"32953888","id":"PMC_32953888","title":"Knockdown of KCNQ1OT1 Inhibits Proliferation, Invasion, and Drug Resistance by Regulating miR-129-5p-Mediated LARP1 in Osteosarcoma.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/32953888","citation_count":12,"is_preprint":false},{"pmid":"38773334","id":"PMC_38773334","title":"eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition.","date":"2024","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38773334","citation_count":11,"is_preprint":false},{"pmid":"37070251","id":"PMC_37070251","title":"O-GlcNAcylated LARP1 positively regulated by circCLNS1A facilitates hepatoblastoma progression through DKK4/β-catenin signalling.","date":"2023","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37070251","citation_count":11,"is_preprint":false},{"pmid":"37985755","id":"PMC_37985755","title":"LHP1-mediated epigenetic buffering of subgenome diversity and defense responses confers genome plasticity and adaptability in allopolyploid wheat.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37985755","citation_count":11,"is_preprint":false},{"pmid":"35863436","id":"PMC_35863436","title":"The amino acid sensor GCN2 suppresses terminal oligopyrimidine (TOP) mRNA translation via La-related protein 1 (LARP1).","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35863436","citation_count":11,"is_preprint":false},{"pmid":"33614632","id":"PMC_33614632","title":"Long Non-coding RNA LINC01969 Promotes Ovarian Cancer by Regulating the miR-144-5p/LARP1 Axis as a Competing Endogenous RNA.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33614632","citation_count":11,"is_preprint":false},{"pmid":"35195778","id":"PMC_35195778","title":"Global analysis of RNA-binding proteins identifies a positive feedback loop between LARP1 and MYC that promotes tumorigenesis.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35195778","citation_count":10,"is_preprint":false},{"pmid":"39111634","id":"PMC_39111634","title":"LARP1, an RNA-binding protein, participates in ovarian cancer cell survival by regulating mitochondrial oxidative phosphorylation in response to the influence of the PI3K/mTOR pathway.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39111634","citation_count":10,"is_preprint":false},{"pmid":"37851576","id":"PMC_37851576","title":"The LARP1 homolog Slr1p controls the stability and expression of proto-5'TOP mRNAs in fission yeast.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37851576","citation_count":8,"is_preprint":false},{"pmid":"21416255","id":"PMC_21416255","title":"Conservation and divergence of plant LHP1 protein sequences and expression patterns in angiosperms and gymnosperms.","date":"2011","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/21416255","citation_count":7,"is_preprint":false},{"pmid":"39016322","id":"PMC_39016322","title":"Enhanced binding of guanylated poly(A) RNA by the LaM domain of LARP1.","date":"2024","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/39016322","citation_count":7,"is_preprint":false},{"pmid":"31398365","id":"PMC_31398365","title":"LARP1 binding to hepatitis C virus particles is correlated with intracellular retention of viral infectivity.","date":"2019","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/31398365","citation_count":7,"is_preprint":false},{"pmid":"40294010","id":"PMC_40294010","title":"EV-D68 cleaves LARP1 and PABPC1 by 3Cpro to redirect host mRNA translation machinery toward its genomic RNA.","date":"2025","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/40294010","citation_count":6,"is_preprint":false},{"pmid":"38067212","id":"PMC_38067212","title":"The MYC-Regulated RNA-Binding Proteins hnRNPC and LARP1 Are Drivers of Multiple Myeloma Cell Growth and Disease Progression and Negatively Predict Patient Survival.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38067212","citation_count":6,"is_preprint":false},{"pmid":"39182167","id":"PMC_39182167","title":"LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder.","date":"2024","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/39182167","citation_count":5,"is_preprint":false},{"pmid":"37961604","id":"PMC_37961604","title":"LARP1 senses free ribosomes to coordinate supply and demand of ribosomal proteins.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37961604","citation_count":5,"is_preprint":false},{"pmid":"38684961","id":"PMC_38684961","title":"Genome-wide investigation of the LARP gene family: focus on functional identification and transcriptome profiling of ZmLARP6c1 in maize pollen.","date":"2024","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/38684961","citation_count":5,"is_preprint":false},{"pmid":"37349870","id":"PMC_37349870","title":"Circ-PDZD8 promotes cell growth and glutamine metabolism in non-small cell lung cancer by enriching LARP1 via sequestering miR-330-5p.","date":"2023","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37349870","citation_count":5,"is_preprint":false},{"pmid":"36694453","id":"PMC_36694453","title":"Long non-coding RNA LINC01270 is an onco-promotor in lung adenocarcinoma by upregulating LARP1 via sponging miR-326.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/36694453","citation_count":5,"is_preprint":false},{"pmid":"38636657","id":"PMC_38636657","title":"Proximity labeling of host factor ANXA3 in HCV infection reveals a novel LARP1 function in viral entry.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38636657","citation_count":5,"is_preprint":false},{"pmid":"39596158","id":"PMC_39596158","title":"Overexpression of LAR1 Suppresses Anthocyanin Biosynthesis by Enhancing Catechin Competition Leading to Promotion of Proanthocyanidin Pathway in Spine Grape (Vitis davidii) Cells.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39596158","citation_count":4,"is_preprint":false},{"pmid":"37006347","id":"PMC_37006347","title":"LARP-assisted synthesis of CsBi3I10 perovskite for efficient lead-free solar cells.","date":"2023","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/37006347","citation_count":4,"is_preprint":false},{"pmid":"38283117","id":"PMC_38283117","title":"LARP1 knockdown inhibits cultured gastric carcinoma cell cycle progression and metastatic behavior.","date":"2024","source":"Open life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38283117","citation_count":3,"is_preprint":false},{"pmid":"36306895","id":"PMC_36306895","title":"Identification and molecular evolution of the La and LARP genes in 16 plant species: A focus on the Gossypium hirsutum.","date":"2022","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36306895","citation_count":3,"is_preprint":false},{"pmid":"33483593","id":"PMC_33483593","title":"The RNA-binding protein LARP1 is dispensable for pancreatic β-cell function and mass.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33483593","citation_count":3,"is_preprint":false},{"pmid":"40818631","id":"PMC_40818631","title":"Targeting LARP1 to mitigate aging in lens epithelial cells: mechanistic insights into mitochondrial dysfunction.","date":"2025","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/40818631","citation_count":3,"is_preprint":false},{"pmid":"41109578","id":"PMC_41109578","title":"Insights into key kinase regulatory network of LARP1 based on co-occurring phosphorylation events.","date":"2025","source":"Biochimica et biophysica acta. Proteins and proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/41109578","citation_count":3,"is_preprint":false},{"pmid":"41287456","id":"PMC_41287456","title":"Conserved Functions of LARP1 Proteins in Eukaryotes.","date":"2025","source":"Wiley interdisciplinary reviews. RNA","url":"https://pubmed.ncbi.nlm.nih.gov/41287456","citation_count":2,"is_preprint":false},{"pmid":"41126333","id":"PMC_41126333","title":"LARP1 acts as a key mediator in preventing angiotensin II-induced cardiac dysfunction and fibrosis.","date":"2025","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/41126333","citation_count":2,"is_preprint":false},{"pmid":"39786317","id":"PMC_39786317","title":"Telocinobufagin suppresses malignant metastasis of undifferentiated thyroid carcinoma via modulation of the LARP1-mTOR pathway.","date":"2025","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39786317","citation_count":2,"is_preprint":false},{"pmid":"39558874","id":"PMC_39558874","title":"The methyltransferase KIAA1429 potentiates cervical cancer tumorigenesis via modulating LARP1 mRNA m6A modification and stability.","date":"2024","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/39558874","citation_count":2,"is_preprint":false},{"pmid":"39190712","id":"PMC_39190712","title":"Comparative analysis of the LARP1 C-terminal DM15 region through Coelomate evolution.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/39190712","citation_count":1,"is_preprint":false},{"pmid":"30942153","id":"PMC_30942153","title":"Gene cloning, expression pattern analysis, and subcellular localization of LIKE HETEROCHROMATIN PROTEIN 1 (LHP1) homologs in chrysanthemum (Chrysanthemum morifolium Ramat.).","date":"2019","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/30942153","citation_count":1,"is_preprint":false},{"pmid":"31801095","id":"PMC_31801095","title":"C-lection by the DM15 Motif Gets LARP1 to the TOP.","date":"2019","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/31801095","citation_count":1,"is_preprint":false},{"pmid":"42143046","id":"PMC_42143046","title":"Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.","date":"2026","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/42143046","citation_count":0,"is_preprint":false},{"pmid":"41623496","id":"PMC_41623496","title":"LAR1 promotes breast carcinogenesis by activating NF-κB signaling pathway through binding and enhancing APOC1 expression.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41623496","citation_count":0,"is_preprint":false},{"pmid":"41278816","id":"PMC_41278816","title":"Larp1 supports brain growth and spatial memory via post-transcriptional control of the translation machinery.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41278816","citation_count":0,"is_preprint":false},{"pmid":"41762867","id":"PMC_41762867","title":"The divergent LARP1 PAM2 motif adopts a non-canonical conformation for MLLE binding.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41762867","citation_count":0,"is_preprint":false},{"pmid":"41934340","id":"PMC_41934340","title":"Deficiency of LARP1 Impairs Spermatogenesis and Leads to Male Subfertility in Mice.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41934340","citation_count":0,"is_preprint":false},{"pmid":"42039457","id":"PMC_42039457","title":"The LARP1 RRM functions as a ribosome responsive regulator of TOP mRNAs.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42039457","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.25.690450","title":"<i>In extracto</i>  cryo-EM reveals eEF2 as a major hibernation factor on 60S and 80S particles","date":"2025-11-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.25.690450","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.09.674968","title":"Lysosomal RNA profiling reveals targeting of specific types of RNAs for degradation","date":"2025-09-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.674968","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.04.626744","title":"The RNA-binding protein PRRC2B preserves 5’ TOP mRNA during starvation to maintain ribosome biogenesis during nutrient recovery","date":"2024-12-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.04.626744","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.06.641895","title":"ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation","date":"2025-03-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.06.641895","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.31.667991","title":"Genome-wide screen for deficiencies modifying Cyclin G-induced developmental instability in Drosophila melanogaster.","date":"2025-08-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.31.667991","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.01.621267","title":"The short conserved region-2 of LARP4 interacts with ribosome-associated RACK1 and promotes translation","date":"2024-11-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.01.621267","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43073,"output_tokens":9565,"usd":0.136347,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19557,"output_tokens":5641,"usd":0.119405,"stage2_stop_reason":"end_turn"},"total_usd":0.255752,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"LARP1 functions as a repressor of TOP mRNA translation downstream of mTORC1: it associates with mTORC1 via RAPTOR, binds the 5'TOP motif of TOP mRNAs in an mTORC1-dependent manner, and competes with eIF4G for TOP mRNA binding. siRNA knockdown of LARP1 attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation.\",\n      \"method\": \"Co-immunoprecipitation (LARP1-RAPTOR), RNA immunoprecipitation, competition binding assays, siRNA knockdown with translation readouts, pharmacological mTORC1 inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, RIP, competition assay, functional siRNA rescue), replicated across several conditions and inhibitors\",\n      \"pmids\": [\"25940091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LARP1 associates with actively translating ribosomes via PABP, associates with mTORC1, and is required for global protein synthesis as well as cell growth and proliferation. It stimulates translation of mRNAs containing a 5'TOP motif.\",\n      \"method\": \"Quantitative proteomic cap-binding screen (m7G cap pulldown), co-immunoprecipitation, polysome profiling, siRNA knockdown with cell growth/proliferation readouts\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomics plus reciprocal Co-IP and functional validation, replicated findings with multiple orthogonal methods\",\n      \"pmids\": [\"24532714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Non-phosphorylated LARP1 interacts with both 5' and 3'UTRs of ribosomal protein mRNAs and inhibits their translation. Phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5'UTRs and relieves translational inhibition. Phosphorylated LARP1 then scaffolds mTORC1 on 3'UTRs of translationally competent RP mRNAs to facilitate mTORC1-dependent translation initiation.\",\n      \"method\": \"In vitro kinase assays (direct substrate validation), deep sequencing of LARP1-bound mRNAs (iCLIP/PAR-CLIP), phospho-mutant analysis, polysome profiling\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay establishing direct substrate relationship, deep sequencing of bound mRNAs, phospho-mutant functional analysis, multiple orthogonal methods\",\n      \"pmids\": [\"28650797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of the human LARP1 DM15 region in complex with a 5'TOP motif, cap analog (m7GTP), and capped cytidine (m7GpppC) show that LARP1 directly binds the m7G cap and adjacent 5'TOP motif. This binding effectively impedes access of eIF4E to the cap, preventing eIF4F assembly on TOP mRNAs.\",\n      \"method\": \"X-ray crystallography (2.6, 1.8, and 1.7 Å resolution structures), cap-binding competition assays, immunoprecipitation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structures with biochemical competition and IP validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28379136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The C-terminal half of LARP1 (containing the DM15 cap-binding domain and an adjacent regulatory region) is necessary and sufficient to control TOP mRNA translation. Purified LARP1 represses TOP mRNA translation in vitro through combined recognition of both the TOP sequence and cap structure.\",\n      \"method\": \"Domain deletion/truncation analysis in cells, in vitro translation repression assay with purified LARP1, binding affinity measurements\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of translational repression with purified protein plus domain mapping in cells, multiple orthogonal methods\",\n      \"pmids\": [\"29244122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"mTORC1 phosphorylates LARP1 in vitro and in vivo at 26 rapamycin-sensitive phospho-serine/threonine residues distributed in 7 clusters. Phosphorylation of a cluster of residues proximal to the DM15 cap-binding region is particularly rapamycin-sensitive and regulates both RNA-binding and translation inhibitory activities. The La module (LaMod) remains constitutively bound to PABP regardless of mTORC1 activation status, while the DM15 'pendular hook' engages the TOP mRNA 5'-end to repress translation only when mTORC1 is inhibited.\",\n      \"method\": \"In vitro mTORC1 kinase assay, quantitative phosphoproteomics (mass spectrometry), phospho-mutant functional analysis, RNA binding assays, rapamycin/torin1 treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay, site-specific phospho-mapping by MS, phospho-mutant functional analysis, multiple orthogonal methods\",\n      \"pmids\": [\"33398329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Molecular dynamics simulations, biophysical assays, and X-ray crystallography reveal the mechanism of DM15 binding to TOP transcripts: residues C-terminal to the m7G-binding site play important roles in cap recognition, and an unusually static pocket that recognizes the +1 cytosine characteristic of TOP transcripts drives binding specificity.\",\n      \"method\": \"X-ray crystallography, molecular dynamics simulations, biophysical binding assays (ITC/SPR)\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures complemented by MD simulations and biophysical assays in a single study\",\n      \"pmids\": [\"31676287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mammalian LARP1 is found in a complex with poly(A)-binding protein (PABP) and eukaryotic initiation factor 4E (eIF4E), and is associated with 60S and 80S ribosomal subunits. siRNA-mediated reduction of LARP1 inhibits global protein synthesis, causes mitotic arrest, and delays cell migration. LARP1 protein localizes to the leading edge of migrating cells and interacts with cytoskeletal components.\",\n      \"method\": \"Co-immunoprecipitation (LARP1-PABP-eIF4E complex), sucrose gradient sedimentation (ribosome association), siRNA knockdown, immunofluorescence localization, cell migration assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ribosome fractionation, functional siRNA knockdown with specific cellular readouts (mitotic arrest, migration), localization imaging\",\n      \"pmids\": [\"20430826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LARP1 specifically recognizes the 3' termini of normal poly(A) tails (identified by proteomics of poly(A)-tail-associated proteins) and stabilizes multiple mRNAs carrying 5'TOP sequences.\",\n      \"method\": \"Proteomics-based identification of poly(A)-terminus-binding proteins, mRNA stability assays following LARP1 manipulation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteomics identification followed by functional mRNA stability assays, single lab\",\n      \"pmids\": [\"23711370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LARP1 interacts with the 3'UTRs of BCL2 and BIK mRNAs, stabilizing BCL2 mRNA but destabilizing BIK mRNA, with the net effect of resisting apoptosis in ovarian cancer cells. LARP1 knockdown reduces cancer cell survival and chemotherapy resistance.\",\n      \"method\": \"RNA immunoprecipitation (RIP), mRNA stability assays, siRNA knockdown, xenograft tumor models, transcriptomic analysis cross-referenced against LARP1 interactome\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP validation of direct 3'UTR interaction, functional stability assays, in vivo xenograft, single lab\",\n      \"pmids\": [\"26717985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LARP1 is complexed to ~3000 mRNAs enriched for cancer pathways. mTOR mRNA is a prominent member of the LARP1 interactome and is stabilized by LARP1. LARP1 promotes cell migration, invasion, and anchorage-independent growth.\",\n      \"method\": \"RNA immunoprecipitation followed by sequencing (RIP-seq), mRNA stability assays, siRNA knockdown with migration/invasion/anchorage-independent growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP-seq for target identification, functional mRNA stability and cellular assays, single lab\",\n      \"pmids\": [\"25531318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The LARP1 La-Module (N-terminal region) binds TOP motifs in a cap-independent manner and also recognizes poly(A) RNA. The La-Module can simultaneously engage TOP motifs and poly(A) RNA, suggesting LARP1 can bridge both ends of TOP mRNAs.\",\n      \"method\": \"Electrophoretic mobility shift assays (EMSA), fluorescence polarization binding assays, in vitro RNA binding with purified La-Module\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays with purified protein, multiple RNA substrates tested, single lab\",\n      \"pmids\": [\"31601159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LARP1 is established as the primary translation regulator of mRNAs with classical TOP motifs genome-wide. The DM15 cap-binding domain and TOP sequence features together determine regulatory potency. Analysis across 16 mammalian tissues reveals constitutive and tissue-specific sets of TOP mRNAs regulated by LARP1.\",\n      \"method\": \"Genome-wide ribosome profiling (Ribo-seq), LARP1 knockout/knockdown coupled with transcriptome-wide translation analysis, quantitative TOPscore metric development\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ribosome profiling in LARP1 KO/KD cells, transcriptome-scale analysis, multiple cell types and tissues, highly rigorous\",\n      \"pmids\": [\"32094190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The isolated La-module of LARP1 mediates poly(A) length protection and mRNA stabilization in HEK293 cells, dependent on a PAM2 motif that binds PABP. A point mutation in the PAM2 motif impairs mRNA stabilization and PABP binding in vivo, but does not impair oligo(A) RNA binding by the purified recombinant La-module in vitro.\",\n      \"method\": \"In vivo mRNA stabilization assay, poly(A) length protection assay, co-immunoprecipitation, point mutagenesis of PAM2 motif, in vitro RNA binding with purified protein\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of specific PAM2 residue with both in vivo and in vitro functional consequences, multiple orthogonal methods\",\n      \"pmids\": [\"33292040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structures of the LARP1 La motif (LaM) domain in complex with poly(A) RNA show the LaM alone (without an RRM) is sufficient for binding poly(A) RNA with submicromolar affinity and specificity, with highest specificity for the RNA 3'-end. Residues Q333, Y336, and F348 are critical for binding. LARP1 La-module binding has functional relevance for poly(A) 3' protection in cells.\",\n      \"method\": \"X-ray crystallography (multiple high-resolution structures with different RNA ligands), ITC binding measurements, mutagenesis of critical residues, quantitative mRNA stabilization assay, poly(A) tail-sequencing in cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures, mutagenesis of critical residues, functional validation in cells, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35979957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TOP mRNA translation positively correlates with poly(A) tail length under mTOR-active conditions. LARP1 is indispensable for mTOR-regulated poly(A) tail-length dynamics: under amino-acid-starved/mTOR-inactive conditions, LARP1 interacts with non-canonical poly(A) polymerases to induce post-transcriptional polyadenylation of TOP mRNA targets, leading to accumulation of long-tailed TOP mRNAs and accelerated ribosomal loading upon nutrient recovery.\",\n      \"method\": \"Poly(A) tail-length sequencing, polysome profiling, co-immunoprecipitation (LARP1 with poly(A) polymerases), LARP1 knockout/knockdown with poly(A) length readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — poly(A) tail sequencing, Co-IP of LARP1 with poly(A) polymerases, functional KO, single lab\",\n      \"pmids\": [\"36288708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LARP1 complexed with the 40S ribosomal subunit protects TOP mRNA regulon from ribophagy under mTOR inhibition, preserving the translatome capacity for ribosome biogenesis resumption when growth conditions return permissive.\",\n      \"method\": \"Ribosome fractionation, RNA sequencing of LARP1-40S complex-associated mRNAs, ribophagy assays, mTOR inhibition experiments\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome fractionation and sequencing, functional ribophagy assay, single lab\",\n      \"pmids\": [\"34818049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PABPC1 is required for the association of LARP1 with its specific mRNA targets. Non-TOP-containing mRNAs bound by LARP1 are in a translationally-repressed state even under control conditions. mRNAs bound by both LARP1 and PABPC1 are translationally repressed.\",\n      \"method\": \"RNA-binding protein capture upon mTOR inhibition (RBP capture-seq), co-immunoprecipitation, PABPC1 depletion with LARP1 mRNA-binding readout, polysome profiling\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RBP capture-seq, functional PABPC1 depletion affecting LARP1-mRNA association, single lab\",\n      \"pmids\": [\"33332560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LARP1 acts as a general decelerator of deadenylation specifically in the 30–60 nucleotide poly(A) length window by preferentially associating with short poly(A) tails. LARP1 depletion causes accelerated deadenylation in the 30–60 nt range and global reduction of mRNA abundance. LARP1 interferes with CCR4-NOT-mediated deadenylation in vitro by forming a ternary complex with PABP and poly(A).\",\n      \"method\": \"Poly(A) tail-length pulse-chase measurement, LARP1 knockdown with poly(A) length and mRNA abundance readouts, in vitro deadenylation assay with purified CCR4-NOT and LARP1\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of CCR4-NOT inhibition by LARP1-PABP-poly(A) ternary complex, poly(A) pulse-chase in cells, KD functional analysis\",\n      \"pmids\": [\"36849640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures reveal that a previously uncharacterized domain of LARP1 directly binds to and occludes the mRNA channel of the 40S ribosomal subunit. Increased availability of free ribosomal subunits promotes 60S joining at the same interface to form LARP1-80S complexes. Contrary to expectations, ribosome binding is NOT required for LARP1-mediated TOP repression or stabilization.\",\n      \"method\": \"Cryo-EM structural determination of LARP1-40S and LARP1-80S complexes, domain mutagenesis to disrupt ribosome binding, functional TOP mRNA repression and stability assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures with functional mutagenesis and negative result (ribosome binding not required for repression/stabilization) validated by independent assays\",\n      \"pmids\": [\"39533057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"4EBP1/2 has a dominant role in translational repression of both 5'TOP and canonical mRNAs during pharmacological mTOR inhibition, whereas LARP1 selectively protects 5'TOP mRNAs from degradation rather than primarily repressing their translation. Single-molecule translation site imaging shows this distinction in living cells.\",\n      \"method\": \"Single-molecule translation site imaging (SunTag reporter), transcriptome-wide mRNA half-life analysis, LARP1 and 4EBP1/2 knockouts/knockdowns\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — single-molecule live-cell imaging plus transcriptome-wide half-life analysis with genetic knockouts, multiple orthogonal methods\",\n      \"pmids\": [\"38363833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"eIF4A1 enhances LARP1-mediated translational repression of TOP mRNAs during mTORC1 inhibition. eIF4A1 preferentially binds TOP mRNAs in a LARP1-dependent manner and increases the interaction between TOP mRNAs and LARP1, thereby strengthening translational repression upon mTORC1 inhibition.\",\n      \"method\": \"RNA pulldown followed by sequencing, ribosome profiling, co-immunoprecipitation, EIF4A1 deletion analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA pulldown-seq, ribosome profiling in EIF4A1 KO cells, Co-IP showing increased LARP1-TOP mRNA interaction, multiple orthogonal methods\",\n      \"pmids\": [\"38773334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GCN2, a second nutrient-sensing kinase, converges on LARP1 to control TOP mRNA translation via two mechanisms: (1) ATF4-dependent transcriptional induction of LARP1 mRNA, and (2) GCN1-mediated recruitment of LARP1 to stalled ribosomes (GCN1 participates in a complex with LARP1 on stalled ribosomes).\",\n      \"method\": \"ChIP-seq (ATF4 binding at LARP1 locus), GCN2 knockout MEFs, co-immunoprecipitation (GCN1-LARP1 on stalled ribosomes), TOP mRNA translation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq for ATF4 target identification, Co-IP for GCN1-LARP1 complex, functional GCN2 KO, single lab\",\n      \"pmids\": [\"35863436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Drosophila Larp exists in a physical complex with and genetically interacts with the translation regulator poly(A)-binding protein (PABP). Larp mutant-derived syncytial embryos show mitotic phenotypes including centrosome migration failure, centrosome detachment from spindle poles, multipolar spindle arrays, and cytokinetic defects. larp mutant males show meiotic defects similar to hypomorphic pAbp alleles.\",\n      \"method\": \"Co-immunoprecipitation (Larp-PABP complex), genetic epistasis (larp and pAbp double mutants), immunofluorescence (mitotic phenotype analysis)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic epistasis and cellular phenotype analysis, Drosophila ortholog study\",\n      \"pmids\": [\"19631203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"C. elegans LARP-1 localizes to germline P bodies, attenuates Ras-MAPK signaling during oogenesis, and larp-1 null mutants have higher than normal levels of selected Ras-MAPK pathway mRNAs and proteins. larp-1 null oogenesis defects are suppressed or enhanced by down- or up-regulating Ras-MAPK pathway. LARP-1 binds RNA in vitro via both its La motif and LARP1 domain.\",\n      \"method\": \"In vitro RNA binding assays (La motif and LARP1 domain), genetic epistasis (larp-1 with Ras-MAPK pathway components), immunofluorescence (P body colocalization), mRNA/protein level analysis in larp-1 nulls\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro RNA binding, genetic epistasis, localization imaging, C. elegans ortholog study\",\n      \"pmids\": [\"18515547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C. elegans LARP-1 promotes oogenesis by repressing fem-3 mRNA. Simultaneous depletion of larp-1 and nos-3 causes germline masculinization dependent on fem-3 activity. fem-3 mRNA levels are increased in larp-1 mutants, indicating LARP-1 suppresses fem-3 expression through a distinct mechanism from NOS-3.\",\n      \"method\": \"RNAi depletion, genetic epistasis (larp-1;nos-3 double knockdown with fem-3 activity requirement), qPCR/Western blot for TRA-1 and FEM protein levels\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined pathway placement, mRNA level analysis, C. elegans ortholog\",\n      \"pmids\": [\"20663921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LARP1 and LARP4 share direct binding to poly(A) and to cytoplasmic PABP (PABPC1) through PAM2 motifs interacting with the MLLE domain of PABP. LARP1 can protect mRNA from deadenylation in a PAM2-dependent manner. The La-module of LARP1 interacts with PABP to stabilize poly(A) tails.\",\n      \"method\": \"Biochemical binding assays (PAM2-MLLE interaction), mRNA stabilization assays, co-immunoprecipitation\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — review synthesizing multiple experimental findings from the lab, supported by primary data from related papers, moderate confidence as a review\",\n      \"pmids\": [\"33522422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"O-GlcNAcylation of LARP1 at Ser672 by O-GlcNAc transferase (OGT) strengthens its binding to circCLNS1A and protects LARP1 from TRIM-25-mediated ubiquitination and proteolysis. LARP1 upregulation leads to DKK4 mRNA stabilization by competitively interacting with PABPC1 to prevent DKK4 mRNA from BTG2-dependent deadenylation and degradation.\",\n      \"method\": \"Co-immunoprecipitation (LARP1-circCLNS1A, LARP1-PABPC1), site-specific mutagenesis (Ser672), protein stability assays, RIP, RNA pull-down, mRNA stability assays, poly(A)-tail length assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — site-specific PTM mutagenesis, Co-IP, RIP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37070251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LARP1 interacts with the 5'UTR of EV-D68 RNA through its LAM domain, and this interaction is crucial for its antiviral function. EV-D68 protease 3Cpro cleaves LARP1 and PABPC1 to counteract LARP1-mediated inhibition of viral translation. Overexpression of LARP1 significantly inhibits EV-D68 replication. mTOR and CDK1 signaling pathways regulate LARP1's binding to viral RNA.\",\n      \"method\": \"Domain mapping (LAM domain interaction with viral 5'UTR), overexpression and siRNA knockdown with viral replication readouts, protease cleavage assays, mTOR/CDK1 pathway inhibitor experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level mapping of viral RNA binding, functional overexpression/KD, protease cleavage mechanism, single lab\",\n      \"pmids\": [\"40294010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The LARP1 PAM2 motif adopts a non-canonical single turn α-helix conformation for MLLE domain binding. Phenylalanine 496 in the PAM2 motif is essential for MLLE binding. NMR chemical shift perturbations defined the MLLE-binding segment within LARP1.\",\n      \"method\": \"NMR spectroscopy (chemical shift perturbation, heteronuclear NOE), isothermal titration calorimetry (ITC), PAM2 mutagenesis, AlphaFold3 modeling\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — NMR and ITC with mutagenesis, single lab, structural characterization of interaction\",\n      \"pmids\": [\"41762867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The LARP1 LaM domain shows preferential binding to poly(A) sequences with single guanine substitutions over unmodified poly(A). Crystal structures of the LARP1 LaM with six different RNA ligands, including singly guanylated sequences, define the structural basis for this selectivity.\",\n      \"method\": \"X-ray crystallography (multiple structures), isothermal titration calorimetry (ITC)\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures and ITC binding measurements, single lab, single study\",\n      \"pmids\": [\"39016322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Brain-specific knockout of Larp1 in mice significantly decreases brain mass, reduces neuronal density, depletes TOP mRNA levels by more than 50%, and selectively removes TOP mRNAs from synapses. Larp1-deficient mice are severely impaired in spatial learning and memory.\",\n      \"method\": \"Brain-specific conditional knockout (Cre-lox), brain mass and neuron density quantification, RNA-seq (TOP mRNA abundance), synaptic fractionation with RNA-seq, behavioral testing (spatial memory)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific CNS phenotypes and molecular readouts, preprint (not yet peer-reviewed)\",\n      \"pmids\": [\"41278816\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LARP1's ribosome-binding region is part of a previously unrecognized RNA recognition motif (RRM) domain that directly interacts with its TOP-binding HEAT repeat (DM15) domain. Ribosome binding is both sufficient in vitro and required in cells for LARP1 to bind, repress, and stabilize TOP mRNAs via unfolding and remodeling of the RRM domain. RRM mutations that disrupt ribosome binding constitutively repress TOPs and compromise cell fitness.\",\n      \"method\": \"Cryo-EM (structural identification of RRM), in vitro ribosome binding assay, RRM mutagenesis, TOP mRNA repression and stability assays in cells, cell fitness/growth assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — cryo-EM structure, in vitro reconstitution, mutagenesis with functional readouts, preprint (not yet peer-reviewed)\",\n      \"pmids\": [\"42039457\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"5'TOP motifs are sufficient to increase mRNA targeting to lysosomes for degradation in a LARP1-dependent manner, establishing a role for LARP1 in selective lysosomal delivery of TOP mRNAs.\",\n      \"method\": \"Lysosomal RNA profiling, LARP1 depletion with lysosomal TOP mRNA accumulation readout, reporter assays with TOP motif\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single preprint, LARP1-dependence shown by depletion but molecular mechanism not fully elaborated in abstract\",\n      \"pmids\": [\"bio_10.1101_2025.09.09.674968\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LARP1 overexpression alleviates angiotensin II-induced cardiac remodeling. LARP1 binds ATP2A2 (SERCA2a) mRNA and enhances its stability; ATP2A2 overexpression reverses hypertrophic and fibrotic changes in LARP1-deficient cardiomyocytes.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pull-down, mRNA stability assay (actinomycin D), AAV9-LARP1 overexpression in vivo, LARP1 KO mice with cardiac phenotype readouts\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, RNA pull-down confirming direct LARP1-ATP2A2 mRNA binding, in vivo KO and overexpression with specific molecular rescue, single lab\",\n      \"pmids\": [\"41126333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LARP1 positively modulates MYC expression by associating with the MYC 3'UTR. Antisense oligonucleotide-mediated blocking of the LARP1–MYC 3'UTR interaction reduces MYC expression. MYC reciprocally modulates LARP1 expression by targeting its enhancer, establishing a positive feedback loop. IGF2BP3 and YBX1 are identified as LARP1-interacting proteins.\",\n      \"method\": \"RIP-seq (LARP1 interactome), antisense oligonucleotide blocking assay, co-immunoprecipitation (LARP1-IGF2BP3, LARP1-YBX1), ChIP (MYC at LARP1 enhancer), mRNA stability/translation assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP-seq, ASO blocking, Co-IP, ChIP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35195778\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LARP1 is an mTORC1-regulated RNA-binding protein that acts as a phosphorylation-sensitive molecular switch for translational control of 5'TOP mRNAs (encoding ribosomal proteins and translation factors): when mTORC1 is inactive, unphosphorylated LARP1 directly binds the m7G cap and adjacent 5'TOP motif via its C-terminal DM15 domain (structural mechanism established by X-ray crystallography), blocking eIF4F assembly; when mTORC1 is active, site-specific phosphorylation of LARP1 (including by Akt/S6K1) releases its repressive 5'-end engagement while its N-terminal La-module simultaneously binds poly(A) tails via a PAM2-PABP interaction to protect mRNAs from CCR4-NOT-mediated deadenylation; additionally, a newly identified RRM domain mediates direct binding to non-translating ribosomal subunits and is required for LARP1 to engage and repress TOP mRNAs, positioning LARP1 as a ribosome-sensing coordinator that couples free ribosome availability to ribosomal protein synthesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LARP1 is an mTORC1-regulated, phosphorylation-sensitive RNA-binding protein that serves as the principal post-transcriptional controller of 5'TOP mRNAs encoding ribosomal proteins and translation factors [#0, #2, #12]. It operates as a bipartite molecular switch: its C-terminal DM15 (HEAT-repeat) domain directly engages both the m7G cap and the adjacent 5'TOP motif, sterically blocking eIF4E/eIF4F assembly and repressing translation when mTORC1 is inactive, with binding specificity driven by an invariant pocket that reads the +1 cytidine characteristic of TOP transcripts [#3, #6, #4]. mTORC1 (and Akt/S6K1) directly phosphorylate LARP1 at multiple clustered serine/threonine residues, and phosphorylation near the DM15 region dissociates LARP1 from the 5'-end to relieve repression [#2, #5]. In parallel, its N-terminal La-module — through a La-motif that binds poly(A) 3'-ends and a PAM2 motif that docks onto the MLLE domain of cytoplasmic PABP — protects poly(A) tails and stabilizes TOP mRNAs, decelerating CCR4-NOT-mediated deadenylation by forming a LARP1–PABP–poly(A) ternary complex [#5, #13, #14, #18, #29]. Beyond translational repression per se, live-cell and transcriptome analyses establish that under mTOR inhibition LARP1's dominant function is selective protection of 5'TOP mRNAs from degradation, preserving the TOP regulon for rapid recovery, while a newly defined RRM domain couples LARP1 to non-translating 40S/80S ribosomal subunits to license TOP engagement [#20, #19, #32]. LARP1 broadly stabilizes and tunes specific transcripts in cancer and tissue contexts — including BCL2/BIK, mTOR, MYC, and SERCA2a (ATP2A2) mRNAs — linking it to apoptosis resistance, proliferation, and cardiac remodeling [#9, #10, #35, #34], and brain-specific loss depletes synaptic TOP mRNAs and impairs spatial memory [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established LARP1 orthologs as RNA-binding, PABP-associated post-transcriptional regulators with conserved developmental roles, framing the protein family before its mammalian translational function was known.\",\n      \"evidence\": \"C. elegans larp-1 genetics, in vitro RNA binding via La motif and LARP1 domain, P-body localization; Drosophila Larp-PABP Co-IP and mitotic/meiotic phenotypes\",\n      \"pmids\": [\"18515547\", \"20663921\", \"19631203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets in mammals not yet defined\", \"TOP mRNA connection not yet made\", \"ortholog phenotypes not mechanistically linked to translation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed mammalian LARP1 physically within the translation apparatus and showed it is required for global protein synthesis, defining it as a translation-associated factor rather than a generic RNA-binding protein.\",\n      \"evidence\": \"Co-IP of LARP1-PABP-eIF4E complex, sucrose-gradient ribosome association (60S/80S), siRNA knockdown with mitotic arrest and migration defects\",\n      \"pmids\": [\"20430826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific mRNA targets not identified\", \"no mechanism for how LARP1 acts on ribosomes\", \"directness of eIF4E association unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the transcriptome-scale LARP1 interactome and linked LARP1 to 5'TOP mRNAs and mTORC1, establishing it as a specific regulator of the TOP regulon and cancer-relevant transcripts.\",\n      \"evidence\": \"Cap-binding proteomic screen, RIP-seq (~3000 mRNAs), polysome profiling, mTORC1 Co-IP, functional siRNA with growth/invasion readouts\",\n      \"pmids\": [\"24532714\", \"25531318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LARP1 activates or represses TOP translation was initially ambiguous\", \"no structural basis for RNA recognition\", \"phosphoregulation not yet shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved LARP1 as an mTORC1-dependent repressor that competes with eIF4G for TOP mRNAs, and extended its target stabilization to apoptosis-regulating mRNAs in cancer.\",\n      \"evidence\": \"LARP1-RAPTOR Co-IP, mTORC1-dependent RIP, eIF4G competition assay, siRNA rescue of rapamycin/Torin1 effects; RIP and stability assays for BCL2/BIK in ovarian cancer with xenografts\",\n      \"pmids\": [\"25940091\", \"26717985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation sites mediating mTORC1 control not mapped\", \"no atomic-resolution view of cap/TOP recognition\", \"reconciliation of repressor vs stabilizer roles incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined LARP1 as a direct mTORC1/Akt-S6K1 substrate whose phosphorylation acts as the switch between repression and translation-competence, providing the kinase logic of the system.\",\n      \"evidence\": \"In vitro kinase assays, iCLIP/PAR-CLIP of LARP1-bound 5' and 3'UTRs, phospho-mutant analysis, polysome profiling\",\n      \"pmids\": [\"28650797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of each phospho-cluster not separated\", \"scaffolding model for mTORC1 on 3'UTRs needs structural support\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the structural and biochemical basis for cap-dependent TOP repression: the DM15 domain binds m7G cap and the adjacent TOP motif to occlude eIF4E, and the C-terminal half is sufficient to repress in vitro.\",\n      \"evidence\": \"X-ray structures of DM15 with m7GTP, m7GpppC and TOP motif; cap-binding competition; purified-LARP1 in vitro repression and domain truncation\",\n      \"pmids\": [\"28379136\", \"29244122\", \"31676287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of phospho-release at the structural level not captured\", \"role of N-terminal La-module in repression not yet integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Bisected the LARP1 mechanism into a constitutive PABP-bound La-module and a regulated DM15 'pendular hook', and demonstrated genome-wide that LARP1 is the primary TOP-mRNA translation regulator.\",\n      \"evidence\": \"mTORC1 phosphoproteomics (26 sites/7 clusters), phospho-mutant RNA-binding assays; La-module EMSA/FP binding to TOP and poly(A); PAM2 mutagenesis with in vivo poly(A) protection; Ribo-seq in LARP1 KO across 16 tissues (TOPscore)\",\n      \"pmids\": [\"33398329\", \"31601159\", \"33292040\", \"32094190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro vs in vivo discrepancy in La-module RNA binding (PAM2 mutant)\", \"how phospho-clusters quantitatively tune affinity unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PABPC1 dependence of LARP1 target selection and a role for LARP1-40S complexes in protecting the TOP regulon from ribophagy, broadening LARP1 from translational control toward mRNA preservation under stress.\",\n      \"evidence\": \"RBP capture-seq with PABPC1 depletion, Co-IP, polysome profiling; ribosome fractionation, RNA-seq of LARP1-40S complexes, ribophagy assays under mTOR inhibition\",\n      \"pmids\": [\"33332560\", \"34818049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"direct ribosome-binding interface not defined here\", \"mechanism coupling 40S to ribophagy protection unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided crystallographic proof that the LaM domain alone binds poly(A) 3'-ends with submicromolar specificity and uncovered LARP1's control of TOP poly(A) dynamics, plus a GCN2/ATF4 input that converges on LARP1.\",\n      \"evidence\": \"LaM-poly(A) crystal structures with mutagenesis and cellular poly(A) protection; poly(A) tail-seq with non-canonical poly(A) polymerase Co-IP; GCN2 KO MEFs, ATF4 ChIP-seq, GCN1-LARP1 Co-IP on stalled ribosomes; MYC 3'UTR feedback loop with IGF2BP3/YBX1 interactors\",\n      \"pmids\": [\"35979957\", \"36288708\", \"35863436\", \"35195778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of non-canonical poly(A) polymerases partnering LARP1 not fully defined\", \"GCN1-LARP1 recruitment mechanism single-lab\", \"MYC feedback loop generality unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reconstituted LARP1 as a sequence-window-specific decelerator of deadenylation, showing it forms a ternary complex with PABP and poly(A) to antagonize CCR4-NOT and broadly stabilize mRNAs.\",\n      \"evidence\": \"Poly(A) pulse-chase in cells, LARP1 KD with poly(A) and abundance readouts, in vitro deadenylation with purified CCR4-NOT and LARP1; O-GlcNAc/TRIM25 PTM control of LARP1 stability with DKK4 mRNA stabilization\",\n      \"pmids\": [\"36849640\", \"37070251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why LARP1 acts preferentially in the 30-60 nt window mechanistically unclear\", \"PTM regulation single-lab and context-specific\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the division of labor in mTOR-inhibited cells (4EBP1/2 represses translation, LARP1 protects TOP mRNAs from degradation), identified the LARP1-40S/80S ribosome interface by cryo-EM, and added eIF4A1 and PAM2-MLLE structural detail.\",\n      \"evidence\": \"Single-molecule SunTag imaging with half-life analysis and KOs; cryo-EM of LARP1-40S/80S with mRNA-channel occlusion and ribosome-binding mutants; eIF4A1 RNA pulldown-seq and Ribo-seq; NMR/ITC of non-canonical PAM2 helix (F496); LaM crystal structures with guanylated poly(A)\",\n      \"pmids\": [\"38363833\", \"39533057\", \"38773334\", \"41762867\", \"39016322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cryo-EM study found ribosome binding NOT required for repression/stabilization, conflicting with later RRM model\", \"physiological role of guanine-tolerant poly(A) recognition unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended LARP1 function to physiology and disease: brain-specific loss depletes synaptic TOP mRNAs and impairs memory; LARP1 stabilizes SERCA2a mRNA to limit cardiac remodeling; and it acts as an antiviral factor cleaved by EV-D68 protease.\",\n      \"evidence\": \"Brain-specific Larp1 cKO mice with RNA-seq, synaptic fractionation and behavior (preprint); LARP1 KO/AAV9 overexpression with ATP2A2 RIP/pull-down rescue in heart; EV-D68 5'UTR-LAM domain mapping with overexpression/KD and 3Cpro cleavage assays\",\n      \"pmids\": [\"41278816\", \"41126333\", \"40294010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Brain study is a preprint\", \"tissue-specific target selectivity mechanisms not defined\", \"antiviral specificity across enteroviruses untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified the LARP1 ribosome-binding region as an RRM domain that intramolecularly engages DM15, proposing that ribosome sensing via RRM remodeling licenses TOP binding, repression and stabilization.\",\n      \"evidence\": \"Cryo-EM identification of RRM, in vitro ribosome-binding reconstitution, RRM mutagenesis with TOP repression/stability and cell-fitness readouts (preprint)\",\n      \"pmids\": [\"42039457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"directly conflicts with prior finding that ribosome binding is not required for repression/stabilization\", \"in vivo relevance of RRM-DM15 interplay untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the structurally defined inputs (phospho-clusters, RRM-ribosome sensing, eIF4A1, PABP) are quantitatively integrated to set the repression-vs-protection balance for individual TOP and non-TOP transcripts across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Conflicting evidence on whether ribosome binding is required for TOP regulation\", \"no unified model linking phosphostate to differential target fate\", \"lysosomal TOP-mRNA delivery role rests on a single low-confidence preprint\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3, 11, 14, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 12, 20]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 2, 4, 12]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 1]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [7, 16, 19]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 18, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 4, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"complexes\": [\n      \"LARP1-PABP-eIF4E cap-binding complex\",\n      \"LARP1-40S/80S ribosome complex\",\n      \"LARP1-PABP-poly(A) ternary complex (anti-CCR4-NOT)\"\n    ],\n    \"partners\": [\n      \"PABPC1\",\n      \"RAPTOR\",\n      \"eIF4E\",\n      \"eIF4A1\",\n      \"GCN1\",\n      \"IGF2BP3\",\n      \"YBX1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}