Affinage

RPS27L

Ribosomal protein eS27-like · UniProt Q71UM5

Length
84 aa
Mass
9.5 kDa
Annotated
2026-04-28
32 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPS27L is a ribosomal protein and direct p53 transcriptional target that functions as a key node linking ribosomal stress sensing to p53 pathway regulation, DNA damage repair, and autophagy. Its N-terminal region binds the MDM2 acidic domain, competitively inhibiting MDM2-mediated p53 ubiquitination and extending p53 half-life; upon RPS27L loss, ribosomal stress stabilizes MDM2, which degrades MDM4 to reduce MDM2–MDM4 E3 ligase activity and activate p53-dependent apoptosis, while elevated MDM2 also sequesters Nbs1 to suppress ATM signaling (PMID:21170087, PMID:25144937, PMID:29396424). RPS27L additionally promotes DNA interstrand cross-link repair by binding and protecting FANCD2/FANCI from p62-mediated autophagic degradation, regulates autophagy through the β-TrCP–DEPTOR–mTORC1 axis, and is itself stabilized by MDM2-mediated neddylation reversed by NEDP1 (PMID:33051438, PMID:30425236, PMID:32779270). Although RPS27L and its paralog RPS27 are functionally interchangeable as ribosomal proteins—with knock-in of one fully rescuing lethality of the other—they are retained in the genome through subfunctionalized, inversely correlated expression patterns across cell types, and RPS27L uniquely undergoes liquid–liquid phase separation via its N-terminal disordered region to interact with IGF1 and promote skeletal muscle growth (PMID:37306301, PMID:40886325).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2006 High

    Establishing that RPS27L is a direct p53 transcriptional target answered the question of how this ribosomal protein gene is regulated in response to genotoxic stress and linked it to apoptotic signaling.

    Evidence Genome-wide chip profiling, EMSA, ChIP, reporter assays, and siRNA in cancer cell lines

    PMID:17057733

    Open questions at the time
    • Mechanism by which RPS27L promotes etoposide-induced apoptosis was undefined
    • Which p53 transactivation domain drives RPS27L induction was unknown
  2. 2007 High

    Demonstrating that RPS27L forms nuclear foci after DNA damage and that its loss converts p53-mediated arrest to apoptosis revealed a checkpoint-maintenance function and a role in sustaining p21 expression.

    Evidence siRNA knockdown, immunofluorescence, cell cycle/flow cytometry, and western blot in human cancer cells

    PMID:18056458

    Open questions at the time
    • Molecular mechanism connecting RPS27L to p21 protein stability was not determined
    • Whether nuclear foci represent ribosomal or extra-ribosomal functions was unclear
  3. 2010 High

    Mapping the RPS27L–MDM2 interaction to the MDM2 acidic domain and showing competitive inhibition of p53 ubiquitination provided a direct molecular mechanism for RPS27L-mediated p53 stabilization.

    Evidence Co-immunoprecipitation with domain mapping, in vivo ubiquitination assay, pulse-chase half-life, immunofluorescence colocalization

    PMID:21170087

    Open questions at the time
    • Structural basis of the RPS27L–MDM2 interaction was not resolved
    • Physiological significance of MDM2-mediated RPS27L degradation in vivo was untested
  4. 2014 High

    An Rps27l knockout mouse demonstrated that loss of RPS27L triggers ribosomal stress–induced MDM2 stabilization, MDM4 degradation, and p53-dependent hematopoietic stem cell apoptosis, establishing the in vivo relevance of the MDM2–MDM4–p53 regulatory axis.

    Evidence Germline mouse knockout with Trp53 genetic epistasis, western blot, flow cytometry, karyotyping, tumor incidence analysis

    PMID:25144937

    Open questions at the time
    • Whether ribosomal stress from RPS27L loss reflects impaired ribosome assembly or a free ribosomal protein signal was not distinguished
    • Contribution of non-p53 pathways to postnatal lethality was not assessed
  5. 2018 High

    Two studies expanded the consequences of RPS27L loss beyond p53: one showed Rps27l-/- radiosensitivity arises partly through MDM2-mediated Nbs1 sequestration that suppresses ATM activation, while the other revealed RPS27L silencing induces autophagy via β-TrCP destabilization, DEPTOR accumulation, and mTORC1 inactivation.

    Evidence Mouse knockout radiation assays with Mdm2 heterozygous rescue and Co-IP (Mdm2–Nbs1); siRNA double knockdown epistasis, autophagy flux, pulse-chase for β-TrCP in human cells and Rps27l-/- MEFs

    PMID:29396424 PMID:30425236

    Open questions at the time
    • Whether the MDM2–Nbs1 interaction is direct or part of a larger complex was not clarified
    • How RPS27L controls β-TrCP protein stability mechanistically remains undefined
  6. 2020 High

    Three discoveries refined RPS27L's molecular network: it directly binds and protects FANCD2/FANCI from autophagic degradation to promote ICL repair; it is stabilized by MDM2-mediated neddylation reversed by NEDP1; and its p53-dependent induction requires at least the 2nd transactivation domain of p53.

    Evidence Reciprocal Co-IP for FANCD2/FANCI with autophagy rescue; in vivo neddylation assay with MDM2/NEDP1 manipulation and half-life assays; ChIP-seq with p53 TAD mutant analysis

    PMID:31834974 PMID:32779270 PMID:33051438

    Open questions at the time
    • Whether neddylation and ubiquitination by MDM2 are competitive modifications on the same sites was not determined
    • Structural basis for RPS27L recognition of FANCD2/FANCI is unknown
    • Relative contributions of neddylation versus ubiquitination to RPS27L steady-state levels in vivo remain unresolved
  7. 2023 High

    Demonstrating that RPS27L and RPS27 are functionally interchangeable ribosomal proteins retained by subfunctionalized expression answered a long-standing question about paralog divergence versus redundancy.

    Evidence Endogenous tagging, ribosome-mRNA profiling, mouse knockout and reciprocal knock-in rescue, developmental staging

    PMID:37306301

    Open questions at the time
    • Whether the extra-ribosomal functions of RPS27L (MDM2 binding, FANCD2 protection) are shared with RPS27 was not tested
    • Cell-type-specific requirements for RPS27L versus RPS27 beyond developmental lethality are unexplored
  8. 2025 Medium

    Identification of RPS27L-driven liquid–liquid phase separation via its N-terminal disordered region and interaction with IGF1 in skeletal muscle established a tissue-specific extra-ribosomal function in myogenesis and muscle growth.

    Evidence Muscle-specific knock-in mouse, LLPS assays, IGF1 RNA/protein interaction, SIX4 transcription factor binding analysis

    PMID:40886325

    Open questions at the time
    • LLPS formation has been demonstrated in one study and awaits independent confirmation
    • Whether phase separation is required for the IGF1 interaction or merely correlates with it is unclear
    • Relevance of LLPS to non-muscle cell types is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: whether RPS27L's extra-ribosomal functions (MDM2 regulation, FANCD2 protection, LLPS) operate from a free cytoplasmic pool or from assembled ribosomes; the structural basis for RPS27L–MDM2 and RPS27L–FANCD2 interactions; and whether the distinct extra-ribosomal activities are functionally coordinated or independent.
  • No structural model of RPS27L in complex with any partner
  • Ribosome-associated versus free-protein pools have not been quantified
  • Integration of neddylation, autophagy, and DNA repair functions into a unified regulatory model is lacking

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
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 R-HSA-9612973 Autophagy 2 R-HSA-1640170 Cell Cycle 1
Partners
BTRCFANCD2FANCIIGF1MDM2MDM4NBNNEDP1
Complex memberships
40S ribosomal subunit

Evidence

Reading pass · 11 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 was identified, and direct p53 binding was demonstrated both in vitro (EMSA) and in vivo (ChIP). Overexpression of RPS27L promoted apoptosis induced by etoposide, while siRNA silencing of RPS27L inhibited it. Genome-wide chip profiling, EMSA, ChIP, luciferase reporter assay, siRNA knockdown, 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. RPS27L positively regulates p21 protein expression to facilitate cell cycle arrest. siRNA knockdown, immunofluorescence/nuclear foci imaging, cell cycle analysis, flow cytometry, western blot for p21 Cancer research High 18056458
2010 The N-terminal region of RPS27L (and RPS27) binds to the central acidic domain of MDM2, forming an in vivo triplex with MDM2-p53 and competing with p53 for MDM2 binding. RPS27L (but not RPS27) is a short-lived MDM2 substrate whose degradation requires the RING or acidic domain of MDM2. Ectopic RPS27L inhibits MDM2-mediated p53 ubiquitination and extends p53 half-life; siRNA silencing of RPS27L decreases p53 levels. Upon p53-activating signals, RPS27L (mainly cytoplasmic) shuttles to the nucleoplasm where it colocalizes with MDM2. Co-immunoprecipitation, domain mapping, in vivo ubiquitination assay, pulse-chase half-life assay, siRNA knockdown, immunofluorescence/colocalization, luciferase reporter for p53 transcriptional activity Oncogene High 21170087
2014 In a mouse knockout model, Rps27l disruption triggers ribosomal stress that stabilizes Mdm2, which then degrades Mdm4, reducing the Mdm2-Mdm4 E3 ligase activity toward p53, leading to p53-dependent apoptotic depletion of hematopoietic stem cells and postnatal death rescued by Trp53 deletion. Under Trp53+/- background, Rps27l disruption drives genomic instability and loss of heterozygosity of Trp53 to promote lymphomagenesis. Mouse germline knockout, genetic epistasis (Rps27l-/-;Trp53-/- double mutant rescue), western blot for Mdm2/Mdm4/p53, flow cytometry of hematopoietic stem cells, tumor incidence analysis, karyotyping eLife High 25144937
2018 RPS27L silencing induces autophagy by inactivating mTORC1 (but not mTORC2). Mechanistically, RPS27L silencing shortens the protein half-life of β-TrCP (a substrate receptor of SCF ubiquitin ligase responsible for DEPTOR degradation), leading to DEPTOR accumulation that inhibits mTORC1. Simultaneous DEPTOR silencing partially rescues autophagy and mTORC1 inactivation caused by RPS27L loss. siRNA knockdown, autophagy assays (LC3-II, autophagic flux), mTORC1/mTORC2 activity assays, pulse-chase half-life assay for β-TrCP, DEPTOR western blot, double knockdown epistasis, Rps27l-/- MEFs Cell death & disease High 30425236
2018 Rps27l inactivation confers radiosensitivity via two mechanisms: (1) imbalanced Mdm2/Mdm4 levels leading to activated p53; (2) elevated Mdm2 binding to Nbs1, which inhibits Nbs1-Atm interaction and subsequent Atm activation, reducing the MRN/Atm DNA damage response signal. Heterozygous deletion of Mdm2 restores the MRN/Atm signal. Mouse knockout (Rps27l-/-;Trp53+/-), radiation sensitivity assay, Co-immunoprecipitation (Mdm2-Nbs1 binding), western blot for MRN/Atm pathway, genetic rescue by Mdm2 heterozygous deletion Cell death & disease High 29396424
2020 RPS27L directly binds to FANCD2 and FANCI (Fanconi anemia proteins). Upon RPS27L knockdown, FANCD2 and FANCI protein levels are reduced due to accelerated degradation via p62-mediated autophagy-lysosome pathway, which impairs ICL repair and reduces FANCD2 foci formation upon mitomycin C treatment. Co-immunoprecipitation (RPS27L-FANCD2/FANCI), siRNA knockdown, immunofluorescence (FANCD2 foci), chloroquine/Beclin1 rescue experiments, MMC sensitivity assay Cell death & disease High 33051438
2020 Both RPS27L and RPS27 are substrates of neddylation by MDM2 E3 ubiquitin ligase and deneddylation by NEDP1. Blockage of neddylation (with MLN4924) destabilizes RPS27L and RPS27 by shortening their protein half-lives. Neddylation stabilizes RPS27L to confer cancer cell survival. In vivo neddylation assay, siRNA knockdown of MDM2/NEDP1, MLN4924 treatment, pulse-chase half-life assay, apoptosis assay upon knockdown/overexpression FASEB journal High 32779270
2023 Rps27 and Rps27l have inversely correlated mRNA abundance across mouse cell types. Rps27- and Rps27l-ribosomes associate preferentially with different mRNA transcripts. Loss-of-function alleles are homozygous lethal at different developmental stages, but expressing Rps27 protein from the endogenous Rps27l locus (or vice versa) completely rescues lethality, demonstrating the two proteins are functionally equivalent and their retention is driven by subfunctionalized expression patterns. Endogenous protein tagging, ribosome-associated mRNA profiling, mouse knockout and knock-in genetic rescue, developmental lethality staging eLife High 37306301
2025 Muscle-specific Rps27l knock-in mice exhibit increased muscle mass, enlarged myofiber size, higher proportion of fast-twitch myofibers, and enhanced muscle regeneration. RPS27L overexpression promotes myoblast proliferation while inhibiting differentiation. The N-terminal intrinsically disordered region of RPS27L facilitates liquid-liquid phase separation (LLPS) and interacts with IGF1 mRNA/protein to regulate myogenesis. SIX4 (a myogenic transcription factor) negatively regulates Rps27l expression. Muscle-specific knock-in mouse model, myofiber size/composition analysis, myoblast overexpression/KD, LLPS assay, RNA-binding/IGF1 interaction assay, SIX4 transcription factor binding assay Advanced science Medium 40886325
2020 RPS27L is identified as a direct transcriptional target of p53 lacking the 1st transactivation domain (Δ1stTAD-p53), dependent on the 2nd TAD transcriptional activation activity, confirming RPS27L induction requires at least the 2nd TAD of p53. ChIP-seq, luciferase reporter assay, p53 mutant transactivation analysis Cancer science Medium 31834974

Source papers

Stage 0 corpus · 32 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 113 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 53 18056458
2014 Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis. eLife 46 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 35 23826192
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
2018 Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis. Cell death & disease 28 30425236
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
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
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 14 40043912
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
2021 The impact of sex on susceptibility to systemic lupus erythematosus and rheumatoid arthritis; a bioinformatics point of view. Cellular signalling 11 34662716
2022 Defective Human SRP Induces Protein Quality Control and Triggers Stress Response. Journal of molecular biology 10 36210597
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
2020 Identification and characterization of the binding sequences and target genes of p53 lacking the 1st transactivation domain. Cancer science 7 31834974
2022 Pre-Conceptional Exposure to Glyphosate Affects the Maternal Hepatic and Ovarian Proteome. Toxicological sciences : an official journal of the Society of Toxicology 6 36173347
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 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
2025 Identification of DNA damage repair-related genes in sepsis using bioinformatics and machine learning: An observational study. Medicine 0 39889168
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