Affinage

RPL27A

Large ribosomal subunit protein uL15 · UniProt P46776

Length
148 aa
Mass
16.6 kDa
Annotated
2026-06-10
42 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPL27A (uL15) is a structural protein of the 60S ribosomal large subunit that contributes to translational competence and ribosome biogenesis, and acts as a sensor coupling ribosomal integrity to the p53 stress response (PMID:2207170, PMID:27374104, PMID:21674502). The protein carries a post-translational hydroxylation at His39 located near the ribosomal E-site, which stabilizes local structure through a hydrogen bond with neighboring His40 and is required for full translational activity; loss of this modification reshapes the translatome toward abundant mRNAs with shorter coding sequences, establishing a role in ribosome heterogeneity and selective mRNA translation (PMID:32492015, PMID:37047141). RPL27A protein stability is governed by ubiquitination at Lys92 and Lys94, and direct ligand binding (martynoside) at the exon 4/5-encoded region reduces this ubiquitination, stabilizing the protein and restoring impaired ribosome biogenesis, mature rRNA abundance, ribosome assembly, and nucleolar integrity (PMID:37481436). Reduced RPL27A levels disrupt 60S subunit biogenesis and nucleolar integrity and trigger ribosomal stress that activates p53 at the protein level through the MDM2 pathway, with consequences including blocked erythroid proliferation/differentiation, hematopoietic stem cell loss, cerebellar ataxia, and pancytopenia in vivo, all rescuable by reducing p53 dosage (PMID:27374104, PMID:21674502, PMID:32535367). In DNA-damage signaling, RPL27A is reduced downstream of ATM and weakens E2F1/p53 binding to MDM2, positioning it upstream of MDM2-p53/E2F1 control (PMID:32535367).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1990 Medium

    Established the basic identity of RPL27A (L27a) as a small basic protein of the 60S large ribosomal subunit, providing the foundational biochemical anchor for all later functional work.

    Evidence Protein sequencing of rat L27a from recombinant cDNA, N-terminal sequencing, Southern and Northern blot

    PMID:2207170

    Open questions at the time
    • No human protein characterized directly
    • No position within 60S architecture defined
    • No functional or regulatory role addressed
  2. 1999 Medium

    Defined the genomic and promoter architecture of human RPL27A, showing it has the TATA-less, Sp1/CpG-island regulatory features typical of ribosomal protein genes and mapping it to 11p15.

    Evidence Gene cloning, sequencing, FISH, and promoter analysis

    PMID:10449908

    Open questions at the time
    • Transcriptional regulators not functionally validated
    • No link from gene structure to protein function
    • Splicing requirement (ATG separated by intron 1) not mechanistically tested
  3. 2011 High

    Placed RPL27A genetically upstream of p53 in ribosomal stress in vivo, showing that reduced RPL27A causes ataxia, pancytopenia, and hematopoietic defects that are p53-dependent.

    Evidence ENU mutagenesis sooty foot ataxia mouse, genetic epistasis with p53 heterozygosity, bone marrow/immunophenotyping

    PMID:21674502

    Open questions at the time
    • Molecular mechanism linking RPL27A loss to p53 activation not resolved
    • Whether ribosome biogenesis defect is the trigger not directly shown
    • c-Kit downregulation mechanism beyond p53-dependence undefined
  4. 2016 Medium

    Connected RPL27A loss to specific cellular outcomes—disrupted 60S biogenesis, nucleolar disintegration, protein-level p53 activation, apoptosis, and blocked erythroid differentiation—identifying it as a miR-595 target.

    Evidence miR-595 luciferase reporter, RPL27A knockdown/overexpression, ribosome subunit analysis, CD34+ differentiation assays

    PMID:27374104

    Open questions at the time
    • Direct biochemical step from biogenesis defect to MDM2/p53 not mapped
    • Erythroid specificity mechanism unexplained
    • No reciprocal validation of the biogenesis vs. p53 ordering
  5. 2020 Medium

    Identified a functional post-translational hydroxylation at His39 required for full ribosomal translational activity, giving the protein a role beyond passive structure.

    Evidence His39Ala/Thr and His40Ala mutagenesis with functional complementation and translation activity assay in HEK293 plus structural modeling

    PMID:32492015

    Open questions at the time
    • Hydroxylating enzyme not identified
    • No crystal structure or in vitro reconstitution
    • Stoichiometry and regulation of hydroxylation unknown
  6. 2020 Medium

    Positioned Rpl27a within ATM-mediated DNA-damage signaling, showing radiation reduces Rpl27a and that this loss alters E2F1/p53 binding to MDM2.

    Evidence In vivo carbon-ion irradiation, proteomics/transcriptomics, GC-1 co-transfection, ATM inhibition, p53 knockout mice

    PMID:32535367

    Open questions at the time
    • Direct physical interactions at MDM2 not demonstrated
    • Mechanism by which RPL27A modulates MDM2 binding unclear
    • Generality beyond spermatogonia untested
  7. 2023 Medium

    Demonstrated that His39 hydroxylation tunes selective mRNA translation, establishing RPL27A as a contributor to ribosome heterogeneity rather than a uniform structural component.

    Evidence His39Ala mutant transfection with polysome profiling and RNA-seq differential analysis in HEK293T

    PMID:37047141

    Open questions at the time
    • Features determining mRNA selectivity not defined
    • Physiological contexts where this matters unknown
    • Link to specific cellular phenotypes not established
  8. 2023 High

    Defined the post-translational stability control of RPL27A, showing K92/K94 ubiquitination drives degradation and that direct ligand binding at exons 4/5 stabilizes the protein and rescues impaired ribosome biogenesis.

    Evidence md-LED in vitro binding screen with martynoside, mutational mapping, ubiquitination proteomics, rRNA/ribosome assembly and nucleolar integrity assays

    PMID:37481436

    Open questions at the time
    • Endogenous E3 ligase and deubiquitinase not identified
    • Physiological ligand (if any) unknown
    • Whether stabilization affects p53 axis not tested
  9. 2022 Low

    Implicated RPL27A as a downstream mediator of an oncogenic tRNA fragment in breast cancer EMT and stemness phenotypes.

    Evidence Luciferase reporter, siRNA knockdown and rescue, migration/invasion/apoptosis and EMT marker assays

    PMID:35030975

    Open questions at the time
    • No direct molecular mechanism for RPL27A's specific contribution established
    • Reporter/knockdown correlative only
    • Not independently validated
  10. 2021 Low

    Associated RPL27A with cancer cell motility in triple-negative breast cancer in the context of EIF2 signaling.

    Evidence siRNA knockdown with migration/invasion assays and single-cell RNA-seq in MDA-MB-231

    PMID:34497807

    Open questions at the time
    • No molecular mechanism for the motility phenotype
    • EIF2 link correlative
    • Knockdown effects may reflect general ribosome loss

Open questions

Synthesis pass · forward-looking unresolved questions
  • The enzyme that installs the His39 hydroxyl, the endogenous E3 ligase/DUB controlling K92/K94 ubiquitination, and the direct biochemical step connecting RPL27A loss to MDM2-p53 activation remain unidentified.
  • No hydroxylase identified
  • No endogenous ubiquitination machinery defined
  • Direct molecular link between ribosomal stress and MDM2/p53 not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005730 nucleolus 2 GO:0005840 ribosome 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-8953897 Cellular responses to stimuli 2
Complex memberships
60S ribosomal large subunit

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 RPL27A (uL15) carries a post-translational hydroxylation modification at His39 residue. Mutation of His39 to Ala or Thr in HEK293 cells reduced the translational activity of ribosomes by ~35% compared to wild-type uL15, establishing that this hydroxylation is required for full translational activity. Structural modeling suggests the hydroxyl group stabilizes local ribosome structure via a hydrogen bond with the imidazole ring of neighboring His40, near the E site of the ribosome. Cell-based mutagenesis (His39Ala, His39Thr, His40Ala substitutions) with functional complementation in HEK293 cells; translational activity assay; structural modeling of human ribosome Molekuliarnaia biologiia Medium 32492015
2023 Mutation of His39 in RPL27A (uL15) to Ala (abolishing hydroxylation) causes specific changes in the translatome in HEK293T cells: ribosomes with the His39Ala mutant preferentially translate more abundant mRNAs with shorter coding sequences, while translation of longer and rarer mRNAs decreases. This demonstrates that hydroxylation at His39 of RPL27A contributes to ribosome heterogeneity and influences selective mRNA translation. Transient transfection of HEK293T cells with wild-type or His39Ala mutant uL15 constructs; RNA-seq of total cellular and polysome-associated mRNAs; differential gene expression analysis International journal of molecular sciences Medium 37047141
2023 Martynoside (MAR) directly binds RPL27A at the region encoded by exons 4 and 5. MAR binding increases RPL27A protein stability by reducing ubiquitination at Lys92 (K92) and Lys94 (K94). Disruption of the MAR-binding residues in RPL27A abolished MAR-induced stabilization. MAR-mediated stabilization of RPL27A rescued 5-FU-impaired ribosome biogenesis, restoring mature rRNA abundance, ribosomal protein levels, ribosome assembly, and nucleolar integrity. mRNA display with library of even-distribution (md-LED) in vitro binding screen; structural and mutational analysis; label-free quantitative ubiquitination proteomics; transcriptomics; ribosome function assays; Western blot Science bulletin High 37481436
2011 A mutation in the mouse Rpl27a gene (sooty foot ataxia mice) activates the p53 tumour suppressor pathway in vivo, causing cerebellar ataxia, pancytopenia, and epidermal hyperpigmentation. These phenotypes are rescued in a p53 haploinsufficient background. Reduced Rpl27a leads to decreased haematopoietic stem cells and p53-dependent c-Kit downregulation, placing Rpl27a upstream of p53 activation in ribosomal stress. ENU mutagenesis screen; genetic epistasis (Rpl27a mutant crossed to p53 heterozygous mice); bone marrow analysis; immunophenotyping The Journal of pathology High 21674502
2020 In mouse spermatogonia, radiation-induced DNA damage reduces Rpl27a expression. Rpl27a reduction weakens binding of E2F1 and p53 to MDM2, causing p53 activation and E2F1 degradation. Co-transfection of ATM and Rpl27a or ATM inhibition could restore Rpl27a expression after carbon ion radiation, placing Rpl27a downstream of ATM-mediated DNA damage signaling and upstream of MDM2-p53/E2F1 pathway. In vivo carbon ion irradiation of mice; comparative proteomics and transcriptomics; immunofluorescence; co-transfection experiments in GC-1 cells; ATM inhibition; p53 knockout mouse model Ecotoxicology and environmental safety Medium 32535367
2016 RPL27A is a direct target of miR-595. Knockdown of RPL27A induces p53 activation, apoptosis, and inhibition of proliferation. RPL27A knockdown also disrupts 60S ribosome subunit biogenesis and nucleolar integrity. In normal CD34+ cells, RPL27A knockdown preferentially blocks erythroid proliferation and differentiation. RPL27A overexpression enhances cellular proliferation without significantly affecting p53 mRNA levels, suggesting p53 protein-level (not transcriptional) regulation. Luciferase reporter gene assay (miR-595 targeting); RPL27A knockdown and overexpression experiments; Western blot; ribosome subunit analysis; differentiation assays in CD34+ cells Oncotarget Medium 27374104
2022 RPL27A is a downstream target of tRF-19-W4PU732S in breast cancer cells. Knockdown of RPL27A partially restored the promoting effects of tRF-19-W4PU732S on BC cell viability, invasion, migration, EMT markers (OCT-4A, SOX2, Vimentin upregulation; E-cadherin downregulation), cancer stem-like cell phenotypes, and suppression of apoptosis, establishing RPL27A as a mediator of these processes. Luciferase reporter assay; Western blot; siRNA knockdown of RPL27A; rescue experiments; cell proliferation, migration, invasion assays; apoptosis assays Bioengineered Low 35030975
1990 Rat ribosomal protein L27a (ortholog of human RPL27A) contains 147 amino acids (after N-terminal methionine removal) with molecular weight 16,476 Da and is a component of the 60S ribosomal large subunit. The N-terminal methionine is removed post-translationally. The gene is present in 18-22 copies in nuclear DNA, and the mRNA is approximately 600 nucleotides in length. Protein sequencing from recombinant cDNA; N-terminal amino acid sequencing; Southern blot hybridization; Northern blot Biochimica et biophysica acta Medium 2207170
1999 The human RPL27A gene (and mouse Rpl27a) contains a specific exon/intron structure where the translational start codon ATG is separated from the main reading frame by the first intron. The promoter region lacks a canonical TATA box but contains Sp1 binding sites, a pyrimidine cluster, and transcriptional regulatory elements Box-A and GABP, located within a CpG island, characteristic of ribosomal protein genes. The human gene maps to chromosome 11p15. Gene cloning and sequencing; FISH; promoter analysis Cytogenetics and cell genetics Medium 10449908
2021 Knockdown of RPL27A in the TNBC cell line MDA-MB-231 significantly reduced cell migration and invasion, establishing a functional role for RPL27A in cancer cell motility. This was identified in the context of EIF2 signaling pathway activation in metastatic TNBC. siRNA knockdown of RPL27A; in vitro cell migration and invasion assays; single-cell RNA-seq analysis Frontiers in cell and developmental biology Low 34497807

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 The herpes simplex virus 1 UL15 gene encodes two proteins and is required for cleavage of genomic viral DNA. Journal of virology 88 7966602
1993 Characterization of a temperature-sensitive mutant of the UL15 open reading frame of herpes simplex virus 1. Journal of virology 88 8331721
1998 Herpes simplex virus type 1 cleavage and packaging proteins UL15 and UL28 are associated with B but not C capsids during packaging. Journal of virology 78 9696839
1997 The U(L)15 gene of herpes simplex virus type 1 contains within its second exon a novel open reading frame that is translated in frame with the U(L)15 gene product. Journal of virology 75 9060619
2002 DNA cleavage and packaging proteins encoded by genes U(L)28, U(L)15, and U(L)33 of herpes simplex virus type 1 form a complex in infected cells. Journal of virology 69 11967295
1995 Cloning, sequencing and expression of the L5, L21, L27a, L28, S5, S9, S10 and S29 human ribosomal protein mRNAs. Biochimica et biophysica acta 66 7772601
1999 Physical and functional interactions between the herpes simplex virus UL15 and UL28 DNA cleavage and packaging proteins. Journal of virology 57 9882384
2003 Herpes simplex virus type 1 portal protein UL6 interacts with the putative terminase subunits UL15 and UL28. Journal of virology 56 12743292
1997 Characterization of ICP6::lacZ insertion mutants of the UL15 gene of herpes simplex virus type 1 reveals the translation of two proteins. Journal of virology 53 9060618
1992 The virulence-determining genomic BamHI fragment 4 of pseudorabies virus contains genes corresponding to the UL15 (partial), UL18, UL19, UL20, and UL21 genes of herpes simplex virus and a putative origin of replication. Virology 45 1333128
2000 Interaction of the herpes simplex virus type 1 packaging protein UL15 with full-length and deleted forms of the UL28 protein. The Journal of general virology 41 11086131
1997 The pseudorabies virus UL28 protein enters the nucleus after coexpression with the herpes simplex virus UL15 protein. Journal of virology 39 9371568
2003 Point mutations in exon I of the herpes simplex virus putative terminase subunit, UL15, indicate that the most conserved residues are essential for cleavage and packaging. Journal of virology 37 12915573
2014 Ribosomal Protein RPL27a Promotes Female Gametophyte Development in a Dose-Dependent Manner. Plant physiology 35 24872379
2006 Herpes simplex virus 1 DNA packaging proteins encoded by UL6, UL15, UL17, UL28, and UL33 are located on the external surface of the viral capsid. Journal of virology 35 16920825
2022 tRF-19-W4PU732S promotes breast cancer cell malignant activity by targeting inhibition of RPL27A (ribosomal protein-L27A). Bioengineered 33 35030975
2021 Ribosome Proteins Represented by RPL27A Mark the Development and Metastasis of Triple-Negative Breast Cancer in Mouse and Human. Frontiers in cell and developmental biology 31 34497807
2006 Linker insertion mutations in the herpes simplex virus type 1 UL28 gene: effects on UL28 interaction with UL15 and UL33 and identification of a second-site mutation in the UL15 gene that suppresses a lethal UL28 mutation. Journal of virology 29 17035316
2011 Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models. The Journal of pathology 25 21674502
1992 The cDNA of UL15, a highly conserved herpes simplex virus 1 gene, effectively replaces the two exons of the wild-type virus. Journal of virology 25 1323715
1991 Sequence analysis of the splice junction in the transcript of herpes simplex virus type 1 gene UL15. Virus research 25 1656627
2004 Quantification of the DNA cleavage and packaging proteins U(L)15 and U(L)28 in A and B capsids of herpes simplex virus type 1. Journal of virology 24 14722291
1990 The primary structure of rat ribosomal proteins: the amino acid sequences of L27a and L28 and corrections in the sequences of S4 and S12. Biochimica et biophysica acta 24 2207170
2008 The UL15 protein of herpes simplex virus type 1 is necessary for the localization of the UL28 and UL33 proteins to viral DNA replication centres. The Journal of general virology 23 18559942
2016 RPL27A is a target of miR-595 and may contribute to the myelodysplastic phenotype through ribosomal dysgenesis. Oncotarget 22 27374104
2011 A mutation in UL15 of herpes simplex virus 1 that reduces packaging of cleaved genomes. Journal of virology 20 21880766
1999 Proteolytic cleavage of the amino terminus of the U(L)15 gene product of herpes simplex virus type 1 is coupled with maturation of viral DNA into unit-length genomes. Journal of virology 20 10482584
2020 Heavy ion radiation-induced DNA damage mediates apoptosis via the Rpl27a-Rpl5-MDM2-p53/E2F1 signaling pathway in mouse spermatogonia. Ecotoxicology and environmental safety 19 32535367
2011 Involvement of ribosomal protein RPL27a in meristem activity and organ development. Plant signaling & behavior 17 21448008
2011 Distribution of allele frequencies at TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A between Japanese Black and four other cattle breeds with differing historical selection for marbling. BMC research notes 12 21251324
2023 Martynoside rescues 5-fluorouracil-impaired ribosome biogenesis by stabilizing RPL27A. Science bulletin 10 37481436
2009 Association of a single nucleotide polymorphism in ribosomal protein L27a gene with marbling in Japanese Black beef cattle. Animal science journal = Nihon chikusan Gakkaiho 10 20163651
2011 Identification of a spliced gene from duck enteritis virus encoding a protein homologous to UL15 of herpes simplex virus 1. Virology journal 7 21466705
1999 Characterization of cDNAs encoding cytoplasmic ribosomal protein L15 and L27a in petunia (Petunia hybrida): primary structures and coordinate expression. Gene 7 9931480
1994 The Drosophila melanogaster homolog of ribosomal protein L27a. Biochemical and biophysical research communications 7 8297386
2020 [Replacement of Hydroxylated His39 in Ribosomal Protein uL15 with Ala or Thr Impairs the Translational Activity of Human Ribosomes]. Molekuliarnaia biologiia 6 32492015
1999 Genomic structure and chromosome location of RPL27A/Rpl27a, the genes encoding human and mouse ribosomal protein L27A. Cytogenetics and cell genetics 6 10449908
2023 Mutation at the Site of Hydroxylation in the Ribosomal Protein uL15 (RPL27a) Causes Specific Changes in the Repertoire of mRNAs Translated in Mammalian Cells. International journal of molecular sciences 4 37047141
1998 The characterization of two Dictyostelium discoideum genes encoding ribosomal proteins with sequence similarity to rat L27a and L37a. Bioscience, biotechnology, and biochemistry 4 9836437
1999 Analysis of the 60 S ribosomal protein L27a (L29) gene of Trypanosoma brucei. International journal for parasitology 3 10404268
1997 Cloning and sequencing of ribosomal protein L27a and a gene similar to human GS1 in Drosophila. Gene 3 9055824
2025 Duck Plague Virus Full-Length UL15 Protein Is a Multifunctional Enzyme Which Not Only Possesses Nuclease Activity but Also Exerts ATPase and DNA-Binding Activity. Veterinary sciences 0 41150132

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