Affinage

RPS27L

Ribosomal protein eS27-like · UniProt Q71UM5

Length
84 aa
Mass
9.5 kDa
Annotated
2026-06-10
35 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPS27L is an evolutionarily conserved ribosomal protein that operates as a stress-responsive node within the MDM2–p53 axis and is itself a direct p53 transcriptional target driven by a consensus p53-binding site in its first intron (PMID:17057733). Mechanistically, the N-terminal region of RPS27L binds the central acidic domain of MDM2 to form a triplex with p53, competing with p53 for MDM2 binding, inhibiting p53 ubiquitination, and extending p53 half-life, while RPS27L is reciprocally a short-lived MDM2 substrate whose turnover is controlled by MDM2-mediated ubiquitination and neddylation, the latter counteracted by NEDP1 deneddylation (PMID:21170087, PMID:32779270). Upon genotoxic stress RPS27L shuttles to the nucleus, forms foci, and is required for intact DNA-damage checkpoints and p21 expression (PMID:18056458, PMID:21170087). In vivo, loss of Rps27l provokes ribosomal stress that stabilizes Mdm2, leading to Mdm4 degradation, reduced E3 activity toward p53, and p53-dependent apoptotic depletion of hematopoietic stem cells, and it impairs the DNA-damage response by enhancing Mdm2 binding to Nbs1 and blocking Nbs1–Atm activation (PMID:25144937, PMID:29396424). RPS27L additionally protects genome stability by binding FANCD2 and FANCI and shielding them from p62-mediated autophagy-lysosomal degradation, enabling interstrand crosslink repair (PMID:33051438), and it restrains autophagy through the β-TrCP–DEPTOR–mTORC1 axis (PMID:30425236). Beyond ribosomal/p53 signaling, RPS27L acts as an RNA-binding protein whose N-terminal intrinsically disordered region drives liquid-liquid phase separation and which interacts with IGF1 to promote myogenesis under negative control by SIX4 (PMID:40886325). Its paralog Rps27 is functionally interchangeable at the protein level, with the two genes differing in cell-type-specific expression and preferential association with distinct ribosome-bound mRNAs rather than in protein activity (PMID:37306301).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 High

    Established that RPS27L is not merely a constitutive ribosomal protein but a direct effector of the p53 program, placing it downstream of p53 in stress responses.

    Evidence ChIP, in vitro p53 binding, luciferase reporter, and siRNA/overexpression apoptosis assays identifying a p53 site in the RPS27L first intron

    PMID:17057733

    Open questions at the time
    • Did not define how RPS27L protein executes its pro-apoptotic effect downstream of p53
    • No mechanistic link to MDM2 yet
  2. 2007 Medium

    Showed RPS27L feeds back into DNA-damage checkpoint control, determining the arrest-versus-apoptosis decision rather than acting solely as a p53 output.

    Evidence siRNA knockdown with nuclear foci imaging, cell cycle/apoptosis assays, and p21 western blot

    PMID:18056458

    Open questions at the time
    • Molecular basis of checkpoint regulation undefined
    • Mechanism of p21 stabilization not established
  3. 2010 High

    Defined the physical and reciprocal regulatory logic of the RPS27L–MDM2–p53 triplex, explaining how RPS27L stabilizes p53 and how MDM2 limits RPS27L.

    Evidence Reciprocal Co-IP, domain mapping, in vivo ubiquitination assay, CHX chase, and subcellular fractionation

    PMID:21170087

    Open questions at the time
    • Stoichiometry and structure of the triplex unresolved
    • Signal triggering nuclear shuttling not identified
  4. 2014 High

    Demonstrated in vivo that RPS27L loss acts through a ribosomal-stress/Mdm2–Mdm4 rebalancing to drive p53-dependent stem cell apoptosis and, in a p53-haploinsufficient context, genomic instability and tumorigenesis.

    Evidence Germline Rps27l knockout mice with Trp53 genetic rescue, Mdm2/Mdm4/p53 western blots, HSC assays, and tumor incidence

    PMID:25144937

    Open questions at the time
    • How RPS27L loss is sensed as ribosomal stress that stabilizes Mdm2 not mechanistically resolved
    • Whether checkpoint and ribosomal functions are separable in vivo unclear
  5. 2018 High

    Identified a second DNA-damage arm in which RPS27L loss enhances Mdm2–Nbs1 binding to suppress MRN/ATM activation, separating p53-axis and ATM-axis contributions to radiosensitivity.

    Evidence Irradiated Rps27l−/−;Trp53+/− mice, Mdm2-Nbs1 Co-IP, pathway western blots, and Mdm2 heterozygous genetic rescue

    PMID:29396424

    Open questions at the time
    • Direct effect of RPS27L on Mdm2–Nbs1 interaction versus indirect via Mdm2 levels not fully dissected
  6. 2018 High

    Extended RPS27L function beyond p53 by showing it controls autophagy and mTORC1 activity through the β-TrCP–DEPTOR axis.

    Evidence siRNA knockdown, CHX chase of β-TrCP, mTOR pathway and LC3 flux assays, DEPTOR co-knockdown rescue, and pharmacological autophagy inhibition

    PMID:30425236

    Open questions at the time
    • How RPS27L regulates β-TrCP stability mechanistically unknown
    • Relationship of this axis to its p53/MDM2 functions unclear
  7. 2020 Medium

    Showed RPS27L and RPS27 stability is set by an MDM2-neddylation/NEDP1-deneddylation cycle, linking neddylation pathway activity to cancer-cell survival.

    Evidence Neddylation assays, CHX chase, MLN4924 inhibition, knockdown and overexpression apoptosis assays

    PMID:32779270

    Open questions at the time
    • Neddylation site(s) not mapped
    • Functional consequence of neddylation versus ubiquitination on RPS27L activity not separated
  8. 2020 High

    Revealed a direct genome-maintenance role in which RPS27L protects FANCD2/FANCI from autophagic degradation to enable interstrand crosslink repair.

    Evidence Co-IP, knockdown with chloroquine/Beclin1 rescue, FANCD2 foci imaging, and mitomycin C sensitivity assay

    PMID:33051438

    Open questions at the time
    • How RPS27L shields FANCD2/FANCI from p62-mediated autophagy not defined
    • Whether this requires the MDM2/p53 axis unknown
  9. 2023 High

    Resolved the paralog relationship by demonstrating that Rps27 and Rps27l proteins are functionally interchangeable, with divergence residing in cell-type-specific expression and mRNA-selective ribosome association rather than protein activity.

    Evidence Protein-swap knock-in rescue of lethality, endogenous tagging, ribosome-mRNA association profiling, and cross-cell-type RNA-seq

    PMID:37306301

    Open questions at the time
    • Determinants of paralog-specific mRNA association unknown
    • Whether non-ribosomal RPS27L functions are paralog-shared not tested
  10. 2025 Medium

    Identified an RNA-binding, phase-separating activity for RPS27L that drives IGF1-dependent myogenesis under SIX4 transcriptional control, broadening its role into tissue growth.

    Evidence Muscle-specific knock-in mice, myofiber phenotyping, LLPS assays, IGF1 interaction studies, and SIX4 transcription assays

    PMID:40886325

    Open questions at the time
    • RNA targets of RPS27L not catalogued
    • Mechanistic link between LLPS and IGF1 signaling undefined
  11. 2025 Medium

    Implicated RPS27L as a stabilized effector of PPP2R2C-driven radioresistance and ferroptosis suppression, connecting its stability control to therapy response in cancer.

    Evidence IP-MS, Co-IP, immunofluorescence, CHX chase with proteasome inhibition, and ferroptosis assays in nasopharyngeal carcinoma cells

    PMID:42115626

    Open questions at the time
    • How RPS27L suppresses ferroptosis mechanistically unknown
    • Whether PPP2R2C regulation intersects the MDM2/p53 axis untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RPS27L's distinct functions — ribosomal incorporation, MDM2/p53 regulation, autophagy/mTORC1 control, FANCD2/FANCI protection, and RNA-binding/LLPS-driven myogenesis — are coordinated within a single protein and partitioned across cell types remains unresolved.
  • No unifying structural or biochemical model links the ribosomal and non-ribosomal activities
  • Whether moonlighting functions occur on or off the ribosome is unknown
  • Cell-type determinants selecting among these functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0003723 RNA binding 1 GO:0005198 structural molecule activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1 GO:0005840 ribosome 1
Complex memberships
ribosome

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 RPS27L is a direct transcriptional target of p53: a consensus p53-binding site in the first intron of RPS27L drives p53-dependent transactivation, demonstrated by direct p53 binding in vitro and in vivo (ChIP), luciferase reporter assays, and sensitivity to dominant-negative p53 mutants. Overexpression of RPS27L promotes, and siRNA silencing inhibits, etoposide-induced apoptosis. ChIP, in vitro binding, luciferase reporter, siRNA knockdown, overexpression with apoptosis assay Oncogene High 17057733
2007 RPS27L is a nuclear protein that forms nuclear foci upon DNA damage. Depletion of RPS27L causes deficiency in DNA damage checkpoints, converting p53-mediated cell cycle arrest to apoptosis, and RPS27L positively regulates p21 protein expression. siRNA knockdown, immunofluorescence/nuclear foci analysis, cell cycle and apoptosis assays, western blot for p21 Cancer research Medium 18056458
2010 The N-terminal region of RPS27L binds to the central acidic domain of MDM2, forming an in vivo triplex complex with MDM2 and p53. RPS27L competes with p53 for MDM2 binding, inhibits MDM2-mediated p53 ubiquitination, and extends p53 protein half-life. RPS27L is itself a short-lived MDM2 substrate whose degradation requires the RING or acidic domain of MDM2. Upon p53-activating signals, RPS27L shuttles from cytoplasm to nucleoplasm where it colocalizes with MDM2. Co-immunoprecipitation, domain-mapping experiments, ubiquitination assay, protein half-life (CHX chase), siRNA knockdown, immunofluorescence/subcellular fractionation Oncogene High 21170087
2014 In vivo mouse knockout shows that Rps27l disruption triggers ribosomal stress that stabilizes Mdm2, which then degrades Mdm4, reducing the Mdm2-Mdm4 E3 ligase activity toward p53 and leading to p53-dependent apoptotic depletion of hematopoietic stem cells and postnatal death rescued by Trp53 deletion. Under Trp53+/- background, Rps27l loss drives genomic instability and Trp53 LOH to promote lymphomagenesis. Germline knockout mice, genetic rescue (Trp53 deletion), western blot for Mdm2/Mdm4/p53 levels, hematopoietic stem cell assays, tumor incidence analysis, genome aneuploidy measurement eLife High 25144937
2018 RPS27L silencing inactivates mTORC1 (but not mTORC2) and induces autophagy via the β-TrCP–DEPTOR axis: loss of RPS27L shortens β-TrCP protein half-life, causing DEPTOR accumulation that inhibits mTORC1. Simultaneous DEPTOR silencing partially rescues autophagy induction, establishing DEPTOR as a causal mediator. Autophagy inhibition with chloroquine or Bafilomycin A1 then triggers apoptosis in RPS27L-silenced cells. siRNA knockdown, protein half-life assay (CHX chase), mTOR pathway western blot, autophagy assays (LC3 flux), rescue experiments (DEPTOR co-knockdown), pharmacological inhibition Cell death & disease High 30425236
2018 Rps27l inactivation causes radiosensitivity via two axes: (1) activated p53 pathway due to imbalanced Mdm2/Mdm4 levels and reduced E3 ligase activity; and (2) elevated Mdm2 binding to Nbs1 that inhibits Nbs1-Atm binding and subsequent Atm activation, reducing MRN/ATM-mediated DNA damage response. Heterozygous Mdm2 deletion restores the MRN/ATM signal. Rps27l−/−;Trp53+/− mice irradiation, western blot for Mdm2/Mdm4/p53/MRN/ATM, Co-IP of Mdm2-Nbs1, genetic rescue (Mdm2 heterozygous deletion), proliferation/apoptosis assays Cell death & disease High 29396424
2020 Both RPS27L and RPS27 are subjected to neddylation by MDM2 E3 ligase and deneddylation by NEDP1. Blockage of neddylation with MLN4924 destabilizes RPS27L and RPS27 by shortening their protein half-lives. Knockdown of RPS27L/RPS27 sensitizes, and ectopic expression desensitizes, cancer cells to MLN4924-induced apoptosis, indicating that neddylation stabilizes these proteins for cancer cell survival. Neddylation assay, CHX chase (protein half-life), MLN4924 pharmacological inhibition, siRNA knockdown, overexpression, apoptosis assays FASEB journal Medium 32779270
2020 RPS27L binds directly to FANCD2 and FANCI. Upon RPS27L knockdown, FANCD2 and FANCI levels decrease due to accelerated degradation via p62-mediated autophagy-lysosome pathway (abrogated by chloroquine or Beclin1 knockdown). RPS27L knockdown suppresses FANCD2 foci formation and impairs ICL repair after mitomycin C treatment. Co-immunoprecipitation, siRNA knockdown, western blot, chloroquine/Beclin1 rescue, FANCD2 immunofluorescence foci, MMC sensitivity assay Cell death & disease High 33051438
2023 Rps27 and Rps27l are functionally equivalent proteins arising from vertebrate whole-genome duplication: expressing Rps27 protein from the endogenous Rps27l locus or vice versa completely rescues loss-of-function lethality. Despite equivalent protein function, the paralogs associate preferentially with different mRNA transcripts in ribosomes and show inversely correlated, cell-type-specific expression patterns, indicating subfunctionalized expression rather than divergent protein function. Endogenous protein tagging, knock-in rescue (protein swap), ribosome-mRNA association profiling, homozygous lethal loss-of-function allele comparison, RNA-seq expression analysis across cell types eLife High 37306301
2025 PPP2R2C physically interacts with RPS27L (confirmed by IP-MS, Co-IP, and immunofluorescence) and stabilizes RPS27L protein by blocking proteasomal degradation (demonstrated by cycloheximide chase and proteasome inhibitor assays). RPS27L knockdown reverses PPP2R2C-mediated radioresistance and suppression of ferroptosis in nasopharyngeal carcinoma cells. IP-MS, Co-IP, immunofluorescence, cycloheximide chase, proteasome inhibition, siRNA knockdown, ferroptosis assays (lipid ROS, MDA, GPX4/SLC7A11 western blot, TEM) Cell death & disease Medium 42115626
2025 RPS27L functions as an RNA-binding protein whose N-terminal intrinsically disordered region mediates liquid-liquid phase separation (LLPS). RPS27L interacts with IGF1 to regulate myogenesis. Muscle-specific Rps27l knock-in mice show increased muscle mass, enlarged myofibers, higher fast-twitch fiber proportion, and enhanced muscle regeneration. RPS27L expression is negatively regulated by the myogenic transcription factor SIX4. Muscle-specific knock-in mice, myofiber size/composition analysis, LLPS assay, Co-IP/interaction studies with IGF1, siRNA/overexpression in myoblasts, SIX4 transcription factor assays Advanced science Medium 40886325
2025 Ribosome-associated factor Nufip1, highly expressed in long-lived bat fibroblasts, associates with ribosomal protein Rps27l and is proposed as an integrator of ribosomal and p53 signaling under DNA replication stress conditions. Comparative transcriptome analysis, co-association/interaction experiment (abstract does not specify Co-IP vs pulldown) Zoological research Low 40407135

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Ribosomal protein S27-like and S27 interplay with p53-MDM2 axis as a target, a substrate and a regulator. Oncogene 115 21170087
2006 Ribosomal protein S27L is a direct p53 target that regulates apoptosis. Oncogene 86 17057733
2007 Ribosomal protein S27-like, a p53-inducible modulator of cell fate in response to genotoxic stress. Cancer research 54 18056458
2014 Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis. eLife 47 25144937
2020 Prediction of breast cancer proteins involved in immunotherapy, metastasis, and RNA-binding using molecular descriptors and artificial neural networks. Scientific reports 41 32444848
2013 Ribosomal protein S27-like in colorectal cancer: a candidate for predicting prognoses. PloS one 36 23826192
2018 Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis. Cell death & disease 31 30425236
2009 Bone marrow cells from patients with Shwachman-Diamond syndrome abnormally express genes involved in ribosome biogenesis and RNA processing. British journal of haematology 31 19438500
2019 Identification of Altered Developmental Pathways in Human Juvenile HD iPSC With 71Q and 109Q Using Transcriptome Profiling. Frontiers in cellular neuroscience 28 30713489
2020 Functional Genomics of the Pediatric Obese Asthma Phenotype Reveal Enrichment of Rho-GTPase Pathways. American journal of respiratory and critical care medicine 27 32255672
2018 Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2-p53 and Mdm2-MRN-ATM axes. Cell death & disease 18 29396424
2025 Pitavastatin and resveratrol bio-nanocomplexes against hyperhomocysteinemia-induced atherosclerosis via blocking ferroptosis-related lipid deposition. Journal of controlled release : official journal of the Controlled Release Society 16 40043912
2020 Neddylation modification of ribosomal protein RPS27L or RPS27 by MDM2 or NEDP1 regulates cancer cell survival. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 32779270
2011 Conservation of multifunctional ribosomal protein metallopanstimulin-1 (RPS27) through complex evolution demonstrates its key role in growth regulation in Archaea, eukaryotic cells, DNA repair, translation and viral replication. Cancer genomics & proteomics 16 21518817
2020 Inactivation of ribosomal protein S27-like impairs DNA interstrand cross-link repair by destabilization of FANCD2 and FANCI. Cell death & disease 12 33051438
2015 Analysis of genes involved in response to doxorubicin and a GD2 ganglioside-specific 14G2a monoclonal antibody in IMR-32 human neuroblastoma cells. Acta biochimica Polonica 12 26284262
2022 Defective Human SRP Induces Protein Quality Control and Triggers Stress Response. Journal of molecular biology 11 36210597
2021 The impact of sex on susceptibility to systemic lupus erythematosus and rheumatoid arthritis; a bioinformatics point of view. Cellular signalling 11 34662716
2023 Subfunctionalized expression drives evolutionary retention of ribosomal protein paralogs Rps27 and Rps27l in vertebrates. eLife 9 37306301
2021 Integrated analysis of RNA-binding proteins in thyroid cancer. PloS one 8 33711033
2023 A MACHINE LEARNING MODEL DERIVED FROM ANALYSIS OF TIME-COURSE GENE-EXPRESSION DATASETS REVEALS TEMPORALLY STABLE GENE MARKERS PREDICTIVE OF SEPSIS MORTALITY. Shock (Augusta, Ga.) 7 37752077
2022 Pre-Conceptional Exposure to Glyphosate Affects the Maternal Hepatic and Ovarian Proteome. Toxicological sciences : an official journal of the Society of Toxicology 7 36173347
2020 Identification and characterization of the binding sequences and target genes of p53 lacking the 1st transactivation domain. Cancer science 7 31834974
2023 High expression of NADH Ubiquinone Oxidoreductase Subunit B11 induces catheter-associated venous thrombosis on continuous blood purification. Medicine 3 38050233
2025 Features and mechanisms of long-lived Myotis somatic fibroblasts in response to DNA replication stress. Zoological research 2 40407135
2025 Identification of DNA damage repair-related genes in sepsis using bioinformatics and machine learning: An observational study. Medicine 1 39889168
2025 DNAzyme-assisted the detection of rps27l mRNA in protein nanopores. Analytica chimica acta 1 39984210
2025 RPS27L Enhances Myogenesis and Muscle Mass by Targeting IGF1 Through Liquid-Liquid Phase Separation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 40886325
2026 S-Doped Carbon Dot Treatment Alters RNA Processing, Translation, and Protein Degradation Pathways in HeLa Cells. Current issues in molecular biology 0 42042009
2026 PPP2R2C confers radioresistance in nasopharyngeal carcinoma by suppressing ferroptosis via RPS27L stabilization. Cell death & disease 0 42115626
2026 Shared gene signatures between rheumatoid arthritis and Sjögren's syndrome. American journal of clinical and experimental immunology 0 42179742
2026 Integrative analysis of bulk and single-nucleus transcriptomes suggests proteostasis- and metabolism-related alterations in the right ventricular outflow tract of non-syndromic Tetralogy of Fallot. Functional & integrative genomics 0 42230411
2025 Identifying the Genetic Ancestry of the Pediatric Obesity-Related Asthma Variant (rs6494395) at Rps27l. Pediatric pulmonology 0 40693564
2025 Spatiotemporal dynamics of RERE in schizophrenia pathogenesis: insights from multi-omics and single-cell sequencing. Schizophrenia (Heidelberg, Germany) 0 41298505
2024 Evaluation of diagnostic value and Mendelian randomization study of appendicitis hub genes obtained by WGCNA analysis. Medicine 0 39252332

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