{"gene":"SLBP","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2003,"finding":"SLBP is phosphorylated on two threonines (T60 and T61 in a TTP sequence, residues 60-62) in late S phase, as determined by mass spectrometry of purified SLBP, triggering its degradation. Mutation of these residues or a cyclin binding site (aa 99-104) stabilizes SLBP in G2 and mitosis. Nuclear extracts from G1 and G2 cells are deficient in histone pre-mRNA processing, restored by recombinant SLBP, identifying SLBP as the only cell cycle-regulated factor required for histone pre-mRNA processing.","method":"Mass spectrometry of purified SLBP from late S-phase cells; site-directed mutagenesis; in vitro pre-mRNA processing assay with nuclear extracts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — MS identification of phosphorylation sites combined with mutagenesis and in vitro processing reconstitution; multiple orthogonal methods in single study","pmids":["12588979"],"is_preprint":false},{"year":2009,"finding":"SLBP knockdown by RNAi results in nuclear retention of properly processed histone mRNA, identifying a role for SLBP in histone mRNA nuclear export. SLBP-depleted cells also show accumulation in S phase and the retained histone mRNA is not rapidly degraded upon inhibition of DNA replication.","method":"RNA interference (RNAi) knockdown in U2OS cells; fluorescence in situ hybridization and cellular fractionation to track histone mRNA localization","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean RNAi knockdown with defined cellular phenotype (nuclear retention), single lab, two orthogonal readouts","pmids":["19155325"],"is_preprint":false},{"year":2016,"finding":"The SCF E3 ubiquitin ligase subunit cyclin F binds SLBP via an atypical CY motif and mediates SLBP ubiquitination and degradation specifically in G2. Mutation of the CY motif prevents G2 degradation. Expression of stable SLBP increases loading of H2AFX mRNA onto polyribosomes, elevating H2A.X levels and sensitizing cells to apoptosis upon genotoxic stress in G2.","method":"Co-immunoprecipitation; site-directed mutagenesis of CY motif; polyribosome fractionation; functional apoptosis assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying E3 ligase, mutagenesis of degron, polyribosome fractionation, and functional consequences; multiple orthogonal methods","pmids":["27773672"],"is_preprint":false},{"year":2004,"finding":"SLBP is a component of the histone mRNP on polyribosomes; histone mRNA from polyribosomes is immunoprecipitated with anti-SLBP antibody. When DNA replication is inhibited, histone mRNA is rapidly degraded but SLBP is relocalized to the nucleus while remaining active for RNA binding and histone pre-mRNA processing.","method":"Immunoprecipitation of polyribosome fractions with anti-SLBP; cycloheximide and replication inhibitor treatments with subcellular fractionation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from polyribosome fractions, subcellular fractionation, single lab with two orthogonal methods","pmids":["15358832"],"is_preprint":false},{"year":2012,"finding":"The prolyl isomerase Pin1 regulates SLBP polyubiquitination via the Ser20/Ser23 phosphodegron in the SLBP N-terminus, and Pin1 together with protein phosphatase 2A (PP2A) can dephosphorylate the phosphothreonine in the conserved TPNK sequence of the SLBP RNA binding domain in vitro, dissociating SLBP from histone mRNA. Pin1 inhibition or knockdown increases histone mRNA stability and stabilizes SLBP, causing nuclear accumulation.","method":"Chemical inhibition and siRNA knockdown of Pin1; in vitro dephosphorylation assay with PP2A; ubiquitination assays; subcellular fractionation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution of dephosphorylation, siRNA knockdown with functional readouts, single lab multiple orthogonal methods","pmids":["22907757"],"is_preprint":false},{"year":2013,"finding":"Crystal structure (2.5 Å) of zebrafish SLIP1 bound to the translation-activation domain of SLBP determined. SLIP1 is a MIF4G-like homodimer that contacts SLBP's translation domain. A SLIP1-binding motif (SBM) was also identified in eIF3g and mRNA-export factor DBP5; pulldown assays confirmed SLIP1 binding to both; crystal structure of SLIP1 bound to DBP5 SBM resolved at 3.25 Å.","method":"X-ray crystallography (2.5 Å and 3.25 Å structures); pulldown assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures solved and confirmed by pulldown assays; two independent crystal structures in same study","pmids":["23804756"],"is_preprint":false},{"year":2017,"finding":"FEM1A, FEM1B, and FEM1C (CUL2-RING E3 ubiquitin ligase substrate recognition subunits) interact with SLBP via distinct degrons in SLBP's N-terminus and mediate SLBP degradation. An SLBP mutant unable to interact with cyclin F and all three FEM1 proteins fails to oscillate during the cell cycle. FEM1-SLBP interaction is conserved in C. elegans and Drosophila; FEM1 depletion in C. elegans upregulates the SLBP ortholog CDL-1 in oocytes.","method":"Co-immunoprecipitation; site-directed mutagenesis of degrons; RNAi in C. elegans; co-immunoprecipitation of orthologs in C. elegans and Drosophila","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis of degrons, conservation confirmed in two model organisms, single lab","pmids":["28118078"],"is_preprint":false},{"year":2016,"finding":"The CUL4 E3 ubiquitin ligase complex CRL4(WDR23) binds and ubiquitylates SLBP in vitro and in vivo. This ubiquitylation activates SLBP function in histone mRNA 3' end processing without affecting SLBP protein levels. Loss of CRL4(WDR23) activity causes depletion of histones, inhibited DNA replication, and growth slowdown.","method":"In vitro ubiquitylation assay; co-immunoprecipitation; RNAi knockdown with histone mRNA processing readouts; mass spectrometry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitylation reconstitution, confirmed in vivo by Co-IP, functional processing assays, multiple orthogonal methods","pmids":["27203182"],"is_preprint":false},{"year":2012,"finding":"The SLBP RNA binding domain contains two binding sites for the histone mRNA hairpin: a helix-turn-helix motif (Glu129-Val158) that recognizes unpaired uridines in the loop, and a second site (Arg180-Pro200) recognizing the second G-C base pair from the stem base. Phosphorylation of threonine in the TPNK sequence between the two sites increases SLBP affinity for histone mRNA by slowing the off-rate, while the adjacent proline acts as a hinge for orienting the second binding site.","method":"NMR spectroscopy; kinetic binding assays; site-directed mutagenesis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural characterization combined with kinetic binding assays and mutagenesis in a single rigorous study","pmids":["22439849"],"is_preprint":false},{"year":2004,"finding":"Phosphorylation at four C-terminal serine residues (in DTAKDSNSDSDSD) of Drosophila SLBP is necessary for histone pre-mRNA processing. Both serine phosphorylation and RNA binding are required for proper folding of the SLBP RNA binding and processing domain (RPD); neither alone is sufficient. The electrostatic effect of phosphorylation can be partially mimicked by glutamic acid substitutions.","method":"31P NMR; circular dichroism; in vitro pre-mRNA processing assays; site-directed mutagenesis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural data, mutagenesis, and in vitro processing assays combined in single study","pmids":["15260483"],"is_preprint":false},{"year":2013,"finding":"SLIP1 is a homodimer that does not bind RNA; phosphorylated SLBP has weak affinity for SLIP1 (Kd ~3 μM) but unphosphorylated SLBP forms a high-affinity 2:2 heterotetramer with SLIP1 (Kd < 0.9 nM) that cannot bind histone mRNA. Sequential binding—phosphorylated SLBP to histone mRNA followed by SLIP1—is required for an active ternary complex. Phosphorylation at Thr171 promotes dissociation of the inactive heterotetramer to a heterodimer. Mutation near the SLIP1 homodimer interface abolished SLBP interaction in vitro and reduced histone mRNA levels in vivo.","method":"Analytical ultracentrifugation; isothermal titration calorimetry; alanine scanning mutagenesis; RNA binding assays; in vivo histone mRNA quantification","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple biophysical methods (AUC, ITC), mutagenesis, and in vivo validation in single study","pmids":["23286197"],"is_preprint":false},{"year":2006,"finding":"SLBP binding to histone pre-mRNA induces structural rearrangements in the 3'-UTR that open hairpin structures embedding the histone downstream element (HDE), making the HDE accessible for U7 snRNA anchoring. EMSA demonstrated that SLBP-induced opening of the HDE facilitates U7 snRNA binding to histone H4-12 pre-mRNA.","method":"RNA structure probing; electrophoretic mobility shift assay (EMSA)","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA structure probing and EMSA, two orthogonal methods, single lab","pmids":["16982637"],"is_preprint":false},{"year":2005,"finding":"RNAi depletion of SLBP causes accumulation of cells in S phase and slows S-phase progression after release from a double-thymidine block. Expression of an RNAi-resistant SLBP restores proper S-phase progression, establishing that SLBP is required for efficient DNA replication, likely through its role in chromatin assembly.","method":"RNAi knockdown; rescue with RNAi-resistant SLBP; cell cycle analysis by flow cytometry","journal":"Biochemical Society transactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown rescued by resistant construct, functional rescue confirms specificity, single lab","pmids":["15916543"],"is_preprint":false},{"year":2022,"finding":"53BP1 functions as a molecular scaffold for nucleoside diphosphate kinase-mediated phosphorylation of ACLY, enhancing ACLY activity. This promotes histone acetylation at the SLBP promoter, driving SLBP transcription. The 53BP1-ACLY-SLBP axis is required for quantitative and qualitative histone biogenesis and genomic integrity.","method":"Co-immunoprecipitation; chromatin immunoprecipitation; ACLY activity assay; SLBP promoter acetylation analysis; loss-of-function experiments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays including ChIP and enzymatic activity, single lab","pmids":["35037047"],"is_preprint":false},{"year":2023,"finding":"Uridylation of the histone mRNA 3' stem-loop by TUT7 weakens SLBP binding affinity (demonstrated by fluorescence polarization and EMSA) while maintaining 3'hExo interactions. Molecular dynamics simulations show that combined uridylation and dephosphorylation of the TPNK motif in SLBP disrupts key RNA-protein interactions, suggesting that trimming by 3'hExo, uridylation, and SLBP dephosphorylation cooperate in the early stages of histone mRNA degradation.","method":"Fluorescence polarization; EMSA; 1-μs molecular dynamics simulations","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two experimental binding methods (FP and EMSA) combined with MD simulations, single lab","pmids":["37516934"],"is_preprint":false},{"year":2021,"finding":"A region of SLBP outside the mRNA-processing domain, overlapping a putative nuclear localization sequence, is required for histone mRNA deposition in the Drosophila oocyte and for histone gene transcription in stage 10B oocytes. SLBP mutants with a 10-amino-acid deletion or mutations in the NLS fail to deposit histone mRNA in the oocyte.","method":"Drosophila genetics; SLBP mutant analysis; in situ hybridization; immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined molecular phenotype, two mutant alleles tested, single lab","pmids":["33408246"],"is_preprint":false},{"year":2025,"finding":"SLBP directly interacts with the RNA helicase UPF1; the unstructured SLBP N-terminus wraps around the UPF1 helicase core at multiple contact sites. SLBP binding to UPF1 impedes UPF1 unwinding activity, but this interaction is critical for efficient histone mRNA decay in cells because UPF1 unwinding of the stem-loop facilitates degradation by 3'hExo. UPF2 binds 3'hExo and, upon activating UPF1, overrides the inhibitory effect of SLBP.","method":"In vitro binding assays; biochemical unwinding assays; cellular decay assays; structural/contact mapping by mutagenesis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and functional unwinding assays reported, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.02.23.639735"],"is_preprint":true},{"year":2025,"finding":"SLBP interacts with FADS2 (identified by IP-MS) and promotes FADS2 expression. SLBP also transcriptionally upregulates and stabilizes SLC7A11, a ferroptosis suppressor, thereby inhibiting lipid peroxidation and ferroptotic cell death in lung adenocarcinoma cells. SLBP-mediated proliferation is functionally dependent on FADS2, as FADS2 inhibition abrogates SLBP-driven growth.","method":"Immunopurification–mass spectrometry (IP-MS); RNA-seq; western blotting; biochemical ferroptosis markers (GSH, MDA, Fe2+); FADS2 inhibition rescue experiments","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — IP-MS identification of interaction and functional assays, single lab, no reciprocal validation of SLBP-FADS2 interaction, cancer cell context may not reflect canonical SLBP function","pmids":["41344497"],"is_preprint":false},{"year":2025,"finding":"In Drosophila, maternal histone mRNAs are polyadenylated with a truncated 3' stem-loop through a noncanonical 3'-end processing mechanism that requires SLBP but not U7 snRNP. These polyadenylated maternal histone transcripts are further stabilized by cytoplasmic poly(A) elongation by Wisp (cytoplasmic poly(A) polymerase), which is required for their translation.","method":"Northern blotting; RNA-seq; genetics (SLBP and U7 snRNP mutants); in situ hybridization","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dissection with multiple mutants and RNA analysis methods, single lab","pmids":["40239992"],"is_preprint":false}],"current_model":"SLBP (stem-loop binding protein) is a cell cycle-regulated, intrinsically disordered protein that binds the conserved 3' stem-loop of replication-dependent histone mRNAs via a two-site RNA binding domain whose affinity is enhanced by phosphorylation of a TPNK threonine; it is the sole cell cycle-regulated factor required for histone pre-mRNA 3' end processing (by facilitating U7 snRNA access to the HDE), and it also participates in histone mRNA nuclear export, translation (via interaction with the SLIP1/MIF4G-like homodimer), and degradation (by recruiting UPF1 and the exoribonuclease 3'hExo); SLBP levels oscillate through the cell cycle via phosphorylation-triggered ubiquitin-mediated proteasomal degradation, with SCF-cyclin F targeting SLBP in G2 via a CY motif, CRL4(WDR23) ubiquitylating SLBP to activate its processing function during S phase, and FEM1A/B/C CUL2 complexes degrading SLBP at other cell cycle stages, while Pin1-mediated prolyl isomerization and PP2A-mediated dephosphorylation of the TPNK motif coordinate SLBP dissociation from histone mRNA with mRNA degradation by the exosome."},"narrative":{"mechanistic_narrative":"SLBP is a cell cycle-regulated RNA-binding protein that coordinates the entire post-transcriptional life cycle of replication-dependent histone mRNAs, linking histone biogenesis to S-phase DNA replication and chromatin assembly [PMID:12588979, PMID:15916543]. It recognizes the conserved 3' stem-loop through a two-site RNA binding domain—a helix-turn-helix that reads unpaired loop uridines and a second site contacting the stem base—with phosphorylation of a threonine in the intervening TPNK motif increasing affinity by slowing the RNA off-rate while the adjacent proline acts as a hinge orienting the second site [PMID:22439849]. In histone pre-mRNA 3' end processing, SLBP is the sole cell cycle-regulated factor required: it restructures the 3'-UTR to expose the histone downstream element for U7 snRNA anchoring, and its processing activity depends both on phosphorylation-coupled folding of the RNA binding/processing domain and on activating ubiquitylation by CRL4(WDR23), which stimulates processing without changing SLBP levels [PMID:12588979, PMID:15260483, PMID:16982637, PMID:27203182]. Beyond processing, SLBP travels with histone mRNA into the cytoplasm, where it remains a component of the polyribosomal histone mRNP and promotes translation through the MIF4G-like SLIP1 homodimer; an ordered assembly in which phosphorylated SLBP binds histone mRNA before recruiting SLIP1 generates the active ternary complex, whereas unphosphorylated SLBP forms an inactive high-affinity SLIP1 heterotetramer [PMID:15358832, PMID:23804756, PMID:23286197]. SLBP also governs histone mRNA decay: dephosphorylation of the TPNK threonine by PP2A together with Pin1, alongside 3' uridylation by TUT7 and trimming by 3'hExo, cooperatively dissociates SLBP and initiates degradation [PMID:22907757, PMID:37516934]. SLBP abundance oscillates through the cell cycle by phosphorylation-triggered, ubiquitin-mediated proteasomal degradation, with SCF–cyclin F targeting SLBP in G2 via a CY motif and FEM1A/B/C–CUL2 complexes contributing degradation at other stages; loss of these degrons abolishes cell cycle oscillation, and stabilized SLBP elevates H2A.X translation and sensitizes cells to genotoxic apoptosis [PMID:12588979, PMID:27773672, PMID:28118078]. SLBP function is conserved across animals, including roles in maternal histone mRNA deposition and noncanonical polyadenylated histone mRNA processing in Drosophila oocytes [PMID:33408246, PMID:40239992].","teleology":[{"year":2003,"claim":"Established that SLBP is the single cell cycle-regulated factor required for histone pre-mRNA 3' end processing and that its level is controlled by phosphorylation-triggered degradation.","evidence":"Mass spectrometry of purified late-S-phase SLBP, degron mutagenesis, and in vitro processing reconstitution with G1/G2 nuclear extracts","pmids":["12588979"],"confidence":"High","gaps":["Did not identify the E3 ligase recognizing the phosphodegron","Mechanism by which SLBP enables processing not resolved at this stage"]},{"year":2004,"claim":"Defined how phosphorylation enables processing—C-terminal serine phosphorylation cooperates with RNA binding to fold the SLBP RNA binding/processing domain.","evidence":"31P NMR, circular dichroism, and in vitro processing assays with phosphomimetic mutants in Drosophila SLBP","pmids":["15260483"],"confidence":"High","gaps":["Folding requirement shown in Drosophila SLBP; human equivalence not directly addressed","Structural detail of the folded domain not resolved"]},{"year":2004,"claim":"Showed SLBP accompanies histone mRNA into the cytoplasm as part of the polyribosomal mRNP and relocalizes to the nucleus while staying RNA-binding-active when replication is blocked.","evidence":"Anti-SLBP immunoprecipitation of polyribosome fractions and subcellular fractionation under replication inhibition","pmids":["15358832"],"confidence":"Medium","gaps":["Did not define the translational machinery SLBP engages","Signal driving nuclear relocalization unknown"]},{"year":2005,"claim":"Linked SLBP function to S-phase progression, demonstrating it is required for efficient DNA replication.","evidence":"RNAi depletion with RNAi-resistant rescue and flow cytometry cell cycle analysis","pmids":["15916543"],"confidence":"Medium","gaps":["Causal step between histone supply and replication slowing not isolated","Chromatin assembly link inferred rather than directly shown"]},{"year":2006,"claim":"Provided the mechanistic basis for processing—SLBP opens 3'-UTR hairpins to expose the histone downstream element for U7 snRNA.","evidence":"RNA structure probing and EMSA on H4-12 pre-mRNA","pmids":["16982637"],"confidence":"Medium","gaps":["Did not resolve how U7 anchoring leads to cleavage","Other processing factors not mapped onto this rearrangement"]},{"year":2009,"claim":"Extended SLBP function to nuclear export, showing it is needed for cytoplasmic delivery of fully processed histone mRNA.","evidence":"RNAi knockdown with FISH and cellular fractionation in U2OS cells","pmids":["19155325"],"confidence":"Medium","gaps":["Export machinery contacted by SLBP not identified","Whether export defect is direct or secondary to processing not resolved"]},{"year":2012,"claim":"Resolved the two-site architecture of the SLBP RNA binding domain and the kinetic role of TPNK phosphorylation in tightening RNA binding.","evidence":"NMR spectroscopy, kinetic binding assays, and site-directed mutagenesis","pmids":["22439849"],"confidence":"High","gaps":["Co-structure with the stem-loop RNA not determined","Did not connect affinity changes to in vivo decay timing"]},{"year":2012,"claim":"Identified Pin1 and PP2A as regulators that dephosphorylate the TPNK threonine to dissociate SLBP from histone mRNA and control SLBP stability via an N-terminal phosphodegron.","evidence":"Pin1 inhibition/knockdown, in vitro PP2A dephosphorylation, ubiquitination assays, and fractionation","pmids":["22907757"],"confidence":"Medium","gaps":["E3 ligase acting on the Ser20/Ser23 phosphodegron not identified here","Kinase counteracting PP2A not defined"]},{"year":2013,"claim":"Defined the structural and ordered-assembly logic of SLBP-driven translation through the SLIP1 homodimer.","evidence":"Crystal structures of zebrafish SLIP1 with SLBP and DBP5 motifs, plus pulldown assays, AUC, ITC, and in vivo mRNA quantification","pmids":["23804756","23286197"],"confidence":"High","gaps":["How the active ternary complex stimulates ribosome recruitment not shown","In vivo phosphorylation switch between heterotetramer and active dimer not directly visualized"]},{"year":2016,"claim":"Identified the G2-specific degradation pathway and its physiological consequence—SCF–cyclin F binds SLBP via a CY motif to limit H2A.X translation and genotoxic sensitivity.","evidence":"Reciprocal Co-IP, CY-motif mutagenesis, polyribosome fractionation, and apoptosis assays","pmids":["27773672"],"confidence":"High","gaps":["Did not account for SLBP turnover outside G2","Kinase priming the CY-motif-coupled degron not defined"]},{"year":2016,"claim":"Revealed a non-degradative ubiquitin signal—CRL4(WDR23) ubiquitylates SLBP to activate processing during S phase without altering its abundance.","evidence":"In vitro and in vivo ubiquitylation, Co-IP, RNAi with processing readouts, and mass spectrometry","pmids":["27203182"],"confidence":"High","gaps":["Ubiquitylated lysines and how they enhance processing not mapped","Interplay with phospho-regulation of processing not resolved"]},{"year":2017,"claim":"Completed the cell cycle degradation network by identifying FEM1A/B/C–CUL2 ligases and showing combined cyclin F and FEM1 degrons are required for SLBP oscillation, with conservation across animals.","evidence":"Co-IP, degron mutagenesis, RNAi in C. elegans, and ortholog Co-IP in C. elegans and Drosophila","pmids":["28118078"],"confidence":"Medium","gaps":["Cell cycle phases governed by each FEM1 paralog not fully partitioned","Signals selecting between FEM1 and cyclin F pathways unknown"]},{"year":2021,"claim":"Showed a non-processing region of SLBP overlapping its NLS is required for maternal histone mRNA deposition and histone gene transcription in oocytes.","evidence":"Drosophila genetics with deletion/NLS mutants, in situ hybridization, and immunofluorescence","pmids":["33408246"],"confidence":"Medium","gaps":["Molecular partners mediating deposition not identified","Mechanism coupling SLBP to histone transcription not resolved"]},{"year":2022,"claim":"Placed SLBP expression downstream of a metabolic-epigenetic axis, with 53BP1-ACLY-driven histone acetylation activating the SLBP promoter.","evidence":"Co-IP, ChIP, ACLY activity assay, promoter acetylation analysis, and loss-of-function","pmids":["35037047"],"confidence":"Medium","gaps":["Direct transcription factors at the SLBP promoter not defined","Generality beyond the cell systems tested unclear"]},{"year":2023,"claim":"Defined the early decay mechanism—uridylation by TUT7 plus TPNK dephosphorylation cooperatively weakens SLBP binding while preserving 3'hExo association.","evidence":"Fluorescence polarization, EMSA, and 1-microsecond molecular dynamics simulations","pmids":["37516934"],"confidence":"Medium","gaps":["Temporal ordering of uridylation versus dephosphorylation in cells not established","Exosome handoff not directly demonstrated"]},{"year":2025,"claim":"Mapped a direct SLBP-UPF1 interaction in which the SLBP N-terminus restrains UPF1 unwinding yet is required for efficient histone mRNA decay, with UPF2-3'hExo overriding the inhibition.","evidence":"In vitro binding and unwinding assays, cellular decay assays, and contact mapping by mutagenesis (preprint)","pmids":["bio_10.1101_2025.02.23.639735"],"confidence":"Medium","gaps":["Awaits peer review","Structural model of the SLBP-UPF1 complex not resolved at high resolution"]},{"year":2025,"claim":"Described a noncanonical maternal histone mRNA pathway requiring SLBP but not U7 snRNP, producing polyadenylated transcripts stabilized by cytoplasmic poly(A) elongation.","evidence":"Drosophila genetics with SLBP and U7 snRNP mutants, northern blotting, RNA-seq, and in situ hybridization","pmids":["40239992"],"confidence":"Medium","gaps":["Factors substituting for U7 snRNP in this pathway not identified","Conservation in mammals not addressed"]},{"year":2025,"claim":"Reported a cancer-context role in which SLBP interacts with FADS2 and upregulates SLC7A11 to suppress ferroptosis and drive proliferation.","evidence":"IP-MS, RNA-seq, western blotting, ferroptosis markers, and FADS2-inhibition rescue in lung adenocarcinoma cells","pmids":["41344497"],"confidence":"Low","gaps":["No reciprocal validation of the SLBP-FADS2 interaction","Cancer cell context may not reflect canonical SLBP function","Mechanism linking SLBP to SLC7A11 transcription not defined"]},{"year":null,"claim":"How the multiple, partly redundant ubiquitin pathways (cyclin F, FEM1A/B/C, CRL4(WDR23)) and phospho/dephospho cycles are temporally integrated to switch SLBP between processing, translation, and decay functions across a single cell cycle remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified kinetic model coordinating degron usage with phosphorylation state","Kinases setting the TPNK and N-terminal degron phosphorylation not fully identified","High-resolution structure of SLBP on the histone stem-loop RNA absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,8,11,14]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[10,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,10,16]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[3,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4,1]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[3,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,11,14,1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,6,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,6,7]}],"complexes":["SLBP-SLIP1 ternary complex on histone mRNA","histone mRNP on polyribosomes"],"partners":["SLIP1","CCNF","FEM1A","FEM1B","FEM1C","WDR23","PIN1","UPF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14493","full_name":"Histone RNA hairpin-binding protein","aliases":["Histone stem-loop-binding protein"],"length_aa":270,"mass_kda":31.3,"function":"RNA-binding protein involved in the histone pre-mRNA processing (PubMed:12588979, PubMed:19155325, PubMed:8957003, PubMed:9049306). Binds the stem-loop structure of replication-dependent histone pre-mRNAs and contributes to efficient 3'-end processing by stabilizing the complex between histone pre-mRNA and U7 small nuclear ribonucleoprotein (snRNP), via the histone downstream element (HDE) (PubMed:12588979, PubMed:19155325, PubMed:8957003, PubMed:9049306). Plays an important role in targeting mature histone mRNA from the nucleus to the cytoplasm and to the translation machinery (PubMed:12588979, PubMed:19155325, PubMed:8957003, PubMed:9049306). Stabilizes mature histone mRNA and could be involved in cell-cycle regulation of histone gene expression (PubMed:12588979, PubMed:19155325, PubMed:8957003, PubMed:9049306). Involved in the mechanism by which growing oocytes accumulate histone proteins that support early embryogenesis (By similarity). Binds to the 5' side of the stem-loop structure of histone pre-mRNAs (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14493/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SLBP","classification":"Common Essential","n_dependent_lines":615,"n_total_lines":1208,"dependency_fraction":0.5091059602649006},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLBP","total_profiled":1310},"omim":[{"mim_id":"617908","title":"ZINC FINGER PROTEIN 473; ZNF473","url":"https://www.omim.org/entry/617908"},{"mim_id":"612072","title":"MIF4G DOMAIN-CONTAINING PROTEIN; MIF4GD","url":"https://www.omim.org/entry/612072"},{"mim_id":"608739","title":"EXORIBONUCLEASE 1; ERI1","url":"https://www.omim.org/entry/608739"},{"mim_id":"602422","title":"STEM-LOOP BINDING PROTEIN; SLBP","url":"https://www.omim.org/entry/602422"},{"mim_id":"194190","title":"WOLF-HIRSCHHORN SYNDROME; WHS","url":"https://www.omim.org/entry/194190"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLBP"},"hgnc":{"alias_symbol":["HBP"],"prev_symbol":[]},"alphafold":{"accession":"Q14493","domains":[{"cath_id":"1.10.8.1120","chopping":"131-196","consensus_level":"high","plddt":96.0906,"start":131,"end":196}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14493","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14493-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14493-F1-predicted_aligned_error_v6.png","plddt_mean":70.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLBP","jax_strain_url":"https://www.jax.org/strain/search?query=SLBP"},"sequence":{"accession":"Q14493","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14493.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14493/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14493"}},"corpus_meta":[{"pmid":"12588979","id":"PMC_12588979","title":"Phosphorylation of stem-loop binding 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/37516934","citation_count":0,"is_preprint":false},{"pmid":"41542534","id":"PMC_41542534","title":"SLBP-independent control of maternal histone mRNA.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41542534","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.23.639735","title":"Molecular mechanisms of recruitment, function and regulation of UPF1 in histone mRNA decay","date":"2025-02-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.23.639735","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.10.637450","title":"Dissecting the role of RNA-binding proteins in early herpes simplex virus 1 transcription using acute protein depletion","date":"2025-02-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.10.637450","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16100,"output_tokens":5365,"usd":0.064388,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13605,"output_tokens":5588,"usd":0.103862,"stage2_stop_reason":"end_turn"},"total_usd":0.16825,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"SLBP is phosphorylated on two threonines (T60 and T61 in a TTP sequence, residues 60-62) in late S phase, as determined by mass spectrometry of purified SLBP, triggering its degradation. Mutation of these residues or a cyclin binding site (aa 99-104) stabilizes SLBP in G2 and mitosis. Nuclear extracts from G1 and G2 cells are deficient in histone pre-mRNA processing, restored by recombinant SLBP, identifying SLBP as the only cell cycle-regulated factor required for histone pre-mRNA processing.\",\n      \"method\": \"Mass spectrometry of purified SLBP from late S-phase cells; site-directed mutagenesis; in vitro pre-mRNA processing assay with nuclear extracts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — MS identification of phosphorylation sites combined with mutagenesis and in vitro processing reconstitution; multiple orthogonal methods in single study\",\n      \"pmids\": [\"12588979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SLBP knockdown by RNAi results in nuclear retention of properly processed histone mRNA, identifying a role for SLBP in histone mRNA nuclear export. SLBP-depleted cells also show accumulation in S phase and the retained histone mRNA is not rapidly degraded upon inhibition of DNA replication.\",\n      \"method\": \"RNA interference (RNAi) knockdown in U2OS cells; fluorescence in situ hybridization and cellular fractionation to track histone mRNA localization\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi knockdown with defined cellular phenotype (nuclear retention), single lab, two orthogonal readouts\",\n      \"pmids\": [\"19155325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The SCF E3 ubiquitin ligase subunit cyclin F binds SLBP via an atypical CY motif and mediates SLBP ubiquitination and degradation specifically in G2. Mutation of the CY motif prevents G2 degradation. Expression of stable SLBP increases loading of H2AFX mRNA onto polyribosomes, elevating H2A.X levels and sensitizing cells to apoptosis upon genotoxic stress in G2.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis of CY motif; polyribosome fractionation; functional apoptosis assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying E3 ligase, mutagenesis of degron, polyribosome fractionation, and functional consequences; multiple orthogonal methods\",\n      \"pmids\": [\"27773672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SLBP is a component of the histone mRNP on polyribosomes; histone mRNA from polyribosomes is immunoprecipitated with anti-SLBP antibody. When DNA replication is inhibited, histone mRNA is rapidly degraded but SLBP is relocalized to the nucleus while remaining active for RNA binding and histone pre-mRNA processing.\",\n      \"method\": \"Immunoprecipitation of polyribosome fractions with anti-SLBP; cycloheximide and replication inhibitor treatments with subcellular fractionation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from polyribosome fractions, subcellular fractionation, single lab with two orthogonal methods\",\n      \"pmids\": [\"15358832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The prolyl isomerase Pin1 regulates SLBP polyubiquitination via the Ser20/Ser23 phosphodegron in the SLBP N-terminus, and Pin1 together with protein phosphatase 2A (PP2A) can dephosphorylate the phosphothreonine in the conserved TPNK sequence of the SLBP RNA binding domain in vitro, dissociating SLBP from histone mRNA. Pin1 inhibition or knockdown increases histone mRNA stability and stabilizes SLBP, causing nuclear accumulation.\",\n      \"method\": \"Chemical inhibition and siRNA knockdown of Pin1; in vitro dephosphorylation assay with PP2A; ubiquitination assays; subcellular fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution of dephosphorylation, siRNA knockdown with functional readouts, single lab multiple orthogonal methods\",\n      \"pmids\": [\"22907757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure (2.5 Å) of zebrafish SLIP1 bound to the translation-activation domain of SLBP determined. SLIP1 is a MIF4G-like homodimer that contacts SLBP's translation domain. A SLIP1-binding motif (SBM) was also identified in eIF3g and mRNA-export factor DBP5; pulldown assays confirmed SLIP1 binding to both; crystal structure of SLIP1 bound to DBP5 SBM resolved at 3.25 Å.\",\n      \"method\": \"X-ray crystallography (2.5 Å and 3.25 Å structures); pulldown assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures solved and confirmed by pulldown assays; two independent crystal structures in same study\",\n      \"pmids\": [\"23804756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FEM1A, FEM1B, and FEM1C (CUL2-RING E3 ubiquitin ligase substrate recognition subunits) interact with SLBP via distinct degrons in SLBP's N-terminus and mediate SLBP degradation. An SLBP mutant unable to interact with cyclin F and all three FEM1 proteins fails to oscillate during the cell cycle. FEM1-SLBP interaction is conserved in C. elegans and Drosophila; FEM1 depletion in C. elegans upregulates the SLBP ortholog CDL-1 in oocytes.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis of degrons; RNAi in C. elegans; co-immunoprecipitation of orthologs in C. elegans and Drosophila\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis of degrons, conservation confirmed in two model organisms, single lab\",\n      \"pmids\": [\"28118078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The CUL4 E3 ubiquitin ligase complex CRL4(WDR23) binds and ubiquitylates SLBP in vitro and in vivo. This ubiquitylation activates SLBP function in histone mRNA 3' end processing without affecting SLBP protein levels. Loss of CRL4(WDR23) activity causes depletion of histones, inhibited DNA replication, and growth slowdown.\",\n      \"method\": \"In vitro ubiquitylation assay; co-immunoprecipitation; RNAi knockdown with histone mRNA processing readouts; mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitylation reconstitution, confirmed in vivo by Co-IP, functional processing assays, multiple orthogonal methods\",\n      \"pmids\": [\"27203182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The SLBP RNA binding domain contains two binding sites for the histone mRNA hairpin: a helix-turn-helix motif (Glu129-Val158) that recognizes unpaired uridines in the loop, and a second site (Arg180-Pro200) recognizing the second G-C base pair from the stem base. Phosphorylation of threonine in the TPNK sequence between the two sites increases SLBP affinity for histone mRNA by slowing the off-rate, while the adjacent proline acts as a hinge for orienting the second binding site.\",\n      \"method\": \"NMR spectroscopy; kinetic binding assays; site-directed mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural characterization combined with kinetic binding assays and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"22439849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Phosphorylation at four C-terminal serine residues (in DTAKDSNSDSDSD) of Drosophila SLBP is necessary for histone pre-mRNA processing. Both serine phosphorylation and RNA binding are required for proper folding of the SLBP RNA binding and processing domain (RPD); neither alone is sufficient. The electrostatic effect of phosphorylation can be partially mimicked by glutamic acid substitutions.\",\n      \"method\": \"31P NMR; circular dichroism; in vitro pre-mRNA processing assays; site-directed mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural data, mutagenesis, and in vitro processing assays combined in single study\",\n      \"pmids\": [\"15260483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SLIP1 is a homodimer that does not bind RNA; phosphorylated SLBP has weak affinity for SLIP1 (Kd ~3 μM) but unphosphorylated SLBP forms a high-affinity 2:2 heterotetramer with SLIP1 (Kd < 0.9 nM) that cannot bind histone mRNA. Sequential binding—phosphorylated SLBP to histone mRNA followed by SLIP1—is required for an active ternary complex. Phosphorylation at Thr171 promotes dissociation of the inactive heterotetramer to a heterodimer. Mutation near the SLIP1 homodimer interface abolished SLBP interaction in vitro and reduced histone mRNA levels in vivo.\",\n      \"method\": \"Analytical ultracentrifugation; isothermal titration calorimetry; alanine scanning mutagenesis; RNA binding assays; in vivo histone mRNA quantification\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple biophysical methods (AUC, ITC), mutagenesis, and in vivo validation in single study\",\n      \"pmids\": [\"23286197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SLBP binding to histone pre-mRNA induces structural rearrangements in the 3'-UTR that open hairpin structures embedding the histone downstream element (HDE), making the HDE accessible for U7 snRNA anchoring. EMSA demonstrated that SLBP-induced opening of the HDE facilitates U7 snRNA binding to histone H4-12 pre-mRNA.\",\n      \"method\": \"RNA structure probing; electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA structure probing and EMSA, two orthogonal methods, single lab\",\n      \"pmids\": [\"16982637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RNAi depletion of SLBP causes accumulation of cells in S phase and slows S-phase progression after release from a double-thymidine block. Expression of an RNAi-resistant SLBP restores proper S-phase progression, establishing that SLBP is required for efficient DNA replication, likely through its role in chromatin assembly.\",\n      \"method\": \"RNAi knockdown; rescue with RNAi-resistant SLBP; cell cycle analysis by flow cytometry\",\n      \"journal\": \"Biochemical Society transactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown rescued by resistant construct, functional rescue confirms specificity, single lab\",\n      \"pmids\": [\"15916543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"53BP1 functions as a molecular scaffold for nucleoside diphosphate kinase-mediated phosphorylation of ACLY, enhancing ACLY activity. This promotes histone acetylation at the SLBP promoter, driving SLBP transcription. The 53BP1-ACLY-SLBP axis is required for quantitative and qualitative histone biogenesis and genomic integrity.\",\n      \"method\": \"Co-immunoprecipitation; chromatin immunoprecipitation; ACLY activity assay; SLBP promoter acetylation analysis; loss-of-function experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays including ChIP and enzymatic activity, single lab\",\n      \"pmids\": [\"35037047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Uridylation of the histone mRNA 3' stem-loop by TUT7 weakens SLBP binding affinity (demonstrated by fluorescence polarization and EMSA) while maintaining 3'hExo interactions. Molecular dynamics simulations show that combined uridylation and dephosphorylation of the TPNK motif in SLBP disrupts key RNA-protein interactions, suggesting that trimming by 3'hExo, uridylation, and SLBP dephosphorylation cooperate in the early stages of histone mRNA degradation.\",\n      \"method\": \"Fluorescence polarization; EMSA; 1-μs molecular dynamics simulations\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two experimental binding methods (FP and EMSA) combined with MD simulations, single lab\",\n      \"pmids\": [\"37516934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A region of SLBP outside the mRNA-processing domain, overlapping a putative nuclear localization sequence, is required for histone mRNA deposition in the Drosophila oocyte and for histone gene transcription in stage 10B oocytes. SLBP mutants with a 10-amino-acid deletion or mutations in the NLS fail to deposit histone mRNA in the oocyte.\",\n      \"method\": \"Drosophila genetics; SLBP mutant analysis; in situ hybridization; immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined molecular phenotype, two mutant alleles tested, single lab\",\n      \"pmids\": [\"33408246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLBP directly interacts with the RNA helicase UPF1; the unstructured SLBP N-terminus wraps around the UPF1 helicase core at multiple contact sites. SLBP binding to UPF1 impedes UPF1 unwinding activity, but this interaction is critical for efficient histone mRNA decay in cells because UPF1 unwinding of the stem-loop facilitates degradation by 3'hExo. UPF2 binds 3'hExo and, upon activating UPF1, overrides the inhibitory effect of SLBP.\",\n      \"method\": \"In vitro binding assays; biochemical unwinding assays; cellular decay assays; structural/contact mapping by mutagenesis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and functional unwinding assays reported, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.02.23.639735\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLBP interacts with FADS2 (identified by IP-MS) and promotes FADS2 expression. SLBP also transcriptionally upregulates and stabilizes SLC7A11, a ferroptosis suppressor, thereby inhibiting lipid peroxidation and ferroptotic cell death in lung adenocarcinoma cells. SLBP-mediated proliferation is functionally dependent on FADS2, as FADS2 inhibition abrogates SLBP-driven growth.\",\n      \"method\": \"Immunopurification–mass spectrometry (IP-MS); RNA-seq; western blotting; biochemical ferroptosis markers (GSH, MDA, Fe2+); FADS2 inhibition rescue experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — IP-MS identification of interaction and functional assays, single lab, no reciprocal validation of SLBP-FADS2 interaction, cancer cell context may not reflect canonical SLBP function\",\n      \"pmids\": [\"41344497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Drosophila, maternal histone mRNAs are polyadenylated with a truncated 3' stem-loop through a noncanonical 3'-end processing mechanism that requires SLBP but not U7 snRNP. These polyadenylated maternal histone transcripts are further stabilized by cytoplasmic poly(A) elongation by Wisp (cytoplasmic poly(A) polymerase), which is required for their translation.\",\n      \"method\": \"Northern blotting; RNA-seq; genetics (SLBP and U7 snRNP mutants); in situ hybridization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dissection with multiple mutants and RNA analysis methods, single lab\",\n      \"pmids\": [\"40239992\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLBP (stem-loop binding protein) is a cell cycle-regulated, intrinsically disordered protein that binds the conserved 3' stem-loop of replication-dependent histone mRNAs via a two-site RNA binding domain whose affinity is enhanced by phosphorylation of a TPNK threonine; it is the sole cell cycle-regulated factor required for histone pre-mRNA 3' end processing (by facilitating U7 snRNA access to the HDE), and it also participates in histone mRNA nuclear export, translation (via interaction with the SLIP1/MIF4G-like homodimer), and degradation (by recruiting UPF1 and the exoribonuclease 3'hExo); SLBP levels oscillate through the cell cycle via phosphorylation-triggered ubiquitin-mediated proteasomal degradation, with SCF-cyclin F targeting SLBP in G2 via a CY motif, CRL4(WDR23) ubiquitylating SLBP to activate its processing function during S phase, and FEM1A/B/C CUL2 complexes degrading SLBP at other cell cycle stages, while Pin1-mediated prolyl isomerization and PP2A-mediated dephosphorylation of the TPNK motif coordinate SLBP dissociation from histone mRNA with mRNA degradation by the exosome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLBP is a cell cycle-regulated RNA-binding protein that coordinates the entire post-transcriptional life cycle of replication-dependent histone mRNAs, linking histone biogenesis to S-phase DNA replication and chromatin assembly [#0, #12]. It recognizes the conserved 3' stem-loop through a two-site RNA binding domain—a helix-turn-helix that reads unpaired loop uridines and a second site contacting the stem base—with phosphorylation of a threonine in the intervening TPNK motif increasing affinity by slowing the RNA off-rate while the adjacent proline acts as a hinge orienting the second site [#8]. In histone pre-mRNA 3' end processing, SLBP is the sole cell cycle-regulated factor required: it restructures the 3'-UTR to expose the histone downstream element for U7 snRNA anchoring, and its processing activity depends both on phosphorylation-coupled folding of the RNA binding/processing domain and on activating ubiquitylation by CRL4(WDR23), which stimulates processing without changing SLBP levels [#0, #9, #11, #7]. Beyond processing, SLBP travels with histone mRNA into the cytoplasm, where it remains a component of the polyribosomal histone mRNP and promotes translation through the MIF4G-like SLIP1 homodimer; an ordered assembly in which phosphorylated SLBP binds histone mRNA before recruiting SLIP1 generates the active ternary complex, whereas unphosphorylated SLBP forms an inactive high-affinity SLIP1 heterotetramer [#3, #5, #10]. SLBP also governs histone mRNA decay: dephosphorylation of the TPNK threonine by PP2A together with Pin1, alongside 3' uridylation by TUT7 and trimming by 3'hExo, cooperatively dissociates SLBP and initiates degradation [#4, #14]. SLBP abundance oscillates through the cell cycle by phosphorylation-triggered, ubiquitin-mediated proteasomal degradation, with SCF–cyclin F targeting SLBP in G2 via a CY motif and FEM1A/B/C–CUL2 complexes contributing degradation at other stages; loss of these degrons abolishes cell cycle oscillation, and stabilized SLBP elevates H2A.X translation and sensitizes cells to genotoxic apoptosis [#0, #2, #6]. SLBP function is conserved across animals, including roles in maternal histone mRNA deposition and noncanonical polyadenylated histone mRNA processing in Drosophila oocytes [#15, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that SLBP is the single cell cycle-regulated factor required for histone pre-mRNA 3' end processing and that its level is controlled by phosphorylation-triggered degradation.\",\n      \"evidence\": \"Mass spectrometry of purified late-S-phase SLBP, degron mutagenesis, and in vitro processing reconstitution with G1/G2 nuclear extracts\",\n      \"pmids\": [\"12588979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the E3 ligase recognizing the phosphodegron\", \"Mechanism by which SLBP enables processing not resolved at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined how phosphorylation enables processing—C-terminal serine phosphorylation cooperates with RNA binding to fold the SLBP RNA binding/processing domain.\",\n      \"evidence\": \"31P NMR, circular dichroism, and in vitro processing assays with phosphomimetic mutants in Drosophila SLBP\",\n      \"pmids\": [\"15260483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Folding requirement shown in Drosophila SLBP; human equivalence not directly addressed\", \"Structural detail of the folded domain not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed SLBP accompanies histone mRNA into the cytoplasm as part of the polyribosomal mRNP and relocalizes to the nucleus while staying RNA-binding-active when replication is blocked.\",\n      \"evidence\": \"Anti-SLBP immunoprecipitation of polyribosome fractions and subcellular fractionation under replication inhibition\",\n      \"pmids\": [\"15358832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the translational machinery SLBP engages\", \"Signal driving nuclear relocalization unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked SLBP function to S-phase progression, demonstrating it is required for efficient DNA replication.\",\n      \"evidence\": \"RNAi depletion with RNAi-resistant rescue and flow cytometry cell cycle analysis\",\n      \"pmids\": [\"15916543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal step between histone supply and replication slowing not isolated\", \"Chromatin assembly link inferred rather than directly shown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the mechanistic basis for processing—SLBP opens 3'-UTR hairpins to expose the histone downstream element for U7 snRNA.\",\n      \"evidence\": \"RNA structure probing and EMSA on H4-12 pre-mRNA\",\n      \"pmids\": [\"16982637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve how U7 anchoring leads to cleavage\", \"Other processing factors not mapped onto this rearrangement\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended SLBP function to nuclear export, showing it is needed for cytoplasmic delivery of fully processed histone mRNA.\",\n      \"evidence\": \"RNAi knockdown with FISH and cellular fractionation in U2OS cells\",\n      \"pmids\": [\"19155325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Export machinery contacted by SLBP not identified\", \"Whether export defect is direct or secondary to processing not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the two-site architecture of the SLBP RNA binding domain and the kinetic role of TPNK phosphorylation in tightening RNA binding.\",\n      \"evidence\": \"NMR spectroscopy, kinetic binding assays, and site-directed mutagenesis\",\n      \"pmids\": [\"22439849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-structure with the stem-loop RNA not determined\", \"Did not connect affinity changes to in vivo decay timing\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Pin1 and PP2A as regulators that dephosphorylate the TPNK threonine to dissociate SLBP from histone mRNA and control SLBP stability via an N-terminal phosphodegron.\",\n      \"evidence\": \"Pin1 inhibition/knockdown, in vitro PP2A dephosphorylation, ubiquitination assays, and fractionation\",\n      \"pmids\": [\"22907757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase acting on the Ser20/Ser23 phosphodegron not identified here\", \"Kinase counteracting PP2A not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the structural and ordered-assembly logic of SLBP-driven translation through the SLIP1 homodimer.\",\n      \"evidence\": \"Crystal structures of zebrafish SLIP1 with SLBP and DBP5 motifs, plus pulldown assays, AUC, ITC, and in vivo mRNA quantification\",\n      \"pmids\": [\"23804756\", \"23286197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the active ternary complex stimulates ribosome recruitment not shown\", \"In vivo phosphorylation switch between heterotetramer and active dimer not directly visualized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the G2-specific degradation pathway and its physiological consequence—SCF–cyclin F binds SLBP via a CY motif to limit H2A.X translation and genotoxic sensitivity.\",\n      \"evidence\": \"Reciprocal Co-IP, CY-motif mutagenesis, polyribosome fractionation, and apoptosis assays\",\n      \"pmids\": [\"27773672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not account for SLBP turnover outside G2\", \"Kinase priming the CY-motif-coupled degron not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a non-degradative ubiquitin signal—CRL4(WDR23) ubiquitylates SLBP to activate processing during S phase without altering its abundance.\",\n      \"evidence\": \"In vitro and in vivo ubiquitylation, Co-IP, RNAi with processing readouts, and mass spectrometry\",\n      \"pmids\": [\"27203182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitylated lysines and how they enhance processing not mapped\", \"Interplay with phospho-regulation of processing not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Completed the cell cycle degradation network by identifying FEM1A/B/C–CUL2 ligases and showing combined cyclin F and FEM1 degrons are required for SLBP oscillation, with conservation across animals.\",\n      \"evidence\": \"Co-IP, degron mutagenesis, RNAi in C. elegans, and ortholog Co-IP in C. elegans and Drosophila\",\n      \"pmids\": [\"28118078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell cycle phases governed by each FEM1 paralog not fully partitioned\", \"Signals selecting between FEM1 and cyclin F pathways unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed a non-processing region of SLBP overlapping its NLS is required for maternal histone mRNA deposition and histone gene transcription in oocytes.\",\n      \"evidence\": \"Drosophila genetics with deletion/NLS mutants, in situ hybridization, and immunofluorescence\",\n      \"pmids\": [\"33408246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners mediating deposition not identified\", \"Mechanism coupling SLBP to histone transcription not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed SLBP expression downstream of a metabolic-epigenetic axis, with 53BP1-ACLY-driven histone acetylation activating the SLBP promoter.\",\n      \"evidence\": \"Co-IP, ChIP, ACLY activity assay, promoter acetylation analysis, and loss-of-function\",\n      \"pmids\": [\"35037047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcription factors at the SLBP promoter not defined\", \"Generality beyond the cell systems tested unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the early decay mechanism—uridylation by TUT7 plus TPNK dephosphorylation cooperatively weakens SLBP binding while preserving 3'hExo association.\",\n      \"evidence\": \"Fluorescence polarization, EMSA, and 1-microsecond molecular dynamics simulations\",\n      \"pmids\": [\"37516934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Temporal ordering of uridylation versus dephosphorylation in cells not established\", \"Exosome handoff not directly demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped a direct SLBP-UPF1 interaction in which the SLBP N-terminus restrains UPF1 unwinding yet is required for efficient histone mRNA decay, with UPF2-3'hExo overriding the inhibition.\",\n      \"evidence\": \"In vitro binding and unwinding assays, cellular decay assays, and contact mapping by mutagenesis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.02.23.639735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Awaits peer review\", \"Structural model of the SLBP-UPF1 complex not resolved at high resolution\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Described a noncanonical maternal histone mRNA pathway requiring SLBP but not U7 snRNP, producing polyadenylated transcripts stabilized by cytoplasmic poly(A) elongation.\",\n      \"evidence\": \"Drosophila genetics with SLBP and U7 snRNP mutants, northern blotting, RNA-seq, and in situ hybridization\",\n      \"pmids\": [\"40239992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Factors substituting for U7 snRNP in this pathway not identified\", \"Conservation in mammals not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported a cancer-context role in which SLBP interacts with FADS2 and upregulates SLC7A11 to suppress ferroptosis and drive proliferation.\",\n      \"evidence\": \"IP-MS, RNA-seq, western blotting, ferroptosis markers, and FADS2-inhibition rescue in lung adenocarcinoma cells\",\n      \"pmids\": [\"41344497\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reciprocal validation of the SLBP-FADS2 interaction\", \"Cancer cell context may not reflect canonical SLBP function\", \"Mechanism linking SLBP to SLC7A11 transcription not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple, partly redundant ubiquitin pathways (cyclin F, FEM1A/B/C, CRL4(WDR23)) and phospho/dephospho cycles are temporally integrated to switch SLBP between processing, translation, and decay functions across a single cell cycle remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified kinetic model coordinating degron usage with phosphorylation state\", \"Kinases setting the TPNK and N-terminal degron phosphorylation not fully identified\", \"High-resolution structure of SLBP on the histone stem-loop RNA absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 8, 11, 14]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [10, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 10, 16]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4, 1]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [3, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 11, 14, 1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 6, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 6, 7]}\n    ],\n    \"complexes\": [\n      \"SLBP-SLIP1 ternary complex on histone mRNA\",\n      \"histone mRNP on polyribosomes\"\n    ],\n    \"partners\": [\n      \"SLIP1\",\n      \"CCNF\",\n      \"FEM1A\",\n      \"FEM1B\",\n      \"FEM1C\",\n      \"WDR23\",\n      \"PIN1\",\n      \"UPF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}