Affinage

RRP12

RRP12-like protein · UniProt Q5JTH9

Length
1297 aa
Mass
143.7 kDa
Annotated
2026-06-10
24 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RRP12 is a conserved HEAT-repeat/Armadillo-domain nucleolar trans-acting factor in small ribosomal subunit (40S) biogenesis, acting across the pathway from early 90S assembly through nuclear export and late cytoplasmic maturation of pre-40S particles (PMID:25474739, PMID:36417864). Within the early 90S pre-ribosome, RRP12 and ENP1 function as a unit that encircles the 18S rRNA 3' major domain, and their premature recruitment is restrained by Cms1 to permit ordered rRNA modification and assembly (PMID:36417864). RRP12 is required for the 90S-to-pre-40S transition and, together with the exportin Crm1, for nucleocytoplasmic export of pre-40S particles (PMID:25474739). After export, RRP12 must be recycled back to the nucleus from cytoplasmic pre-40S intermediates, a step that depends on the pre-40S kinase Rio2 and on CK1δ/CK1ε activity (PMID:24424021, PMID:21097556); release of RRP12 from late precursors is gated by assembly of the S0-cluster of ribosomal proteins at the subunit neck (PMID:30653518). Its nucleolar entrapment under nutritional, osmotic, and oxidative stress places RRP12-dependent pre-40S export under TOR pathway control (PMID:18755838). Beyond ribosome synthesis, yeast Rrp12 acts as a cofactor for Kap121-dependent nuclear import of ribonucleotide reductase subunits, coupling the cell cycle and DNA damage response to dNTP supply (PMID:21482668). In human cells RRP12 suppresses p53 stability during nucleolar stress to promote survival (PMID:26499779) and supports proliferation and ZEB1-mediated EMT in colorectal cancer (PMID:37969827). Biallelic loss-of-function variants in RRP12 cause autosomal recessive brain calcifications, with patient fibroblasts showing reduced RRP12 and abnormal nucleolar morphology (PMID:41059649).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 High

    Established that Rrp12 is a stress- and TOR-responsive pre-40S export factor, linking ribosome subunit transport to nutrient signaling.

    Evidence Fluorescence localization under nutritional/osmotic/oxidative stress and rapamycin, plus pre-40S export assays and TOR epistasis in yeast

    PMID:18755838

    Open questions at the time
    • Direct molecular signal coupling TOR to Rrp12 relocalization not defined
    • Export receptor partners not identified in this study
  2. 2010 High

    Placed human RRP12 in the late cytoplasmic 40S maturation pathway downstream of the kinase Rio2, which is required for its recycling back to the nucleus.

    Evidence TAP purification of pre-40S particles with inducible Rio2 depletion and immunofluorescence localization in human cells

    PMID:21097556

    Open questions at the time
    • Whether Rio2 acts directly on RRP12 not shown
    • Recycling import receptor not identified
  3. 2011 High

    Identified a ribosome-independent role for Rrp12 as a Kap121 import cofactor for ribonucleotide reductase subunits, coupling ribosome biogenesis machinery to dNTP homeostasis and the DNA damage response.

    Evidence Yeast functional screen, genetic epistasis, nuclear import assays, and RNR localization analysis

    PMID:21482668

    Open questions at the time
    • Direct Rrp12-Kap121 binding interface not mapped
    • Whether human RRP12 retains this import function untested
  4. 2014 High

    Demonstrated that CK1δ/CK1ε activity is required to recycle RRP12 and other trans-acting factors from cytoplasmic pre-40S particles, defining a kinase-dependent late maturation step.

    Evidence Tandem affinity purification of pre-40S particles with shRNA co-depletion of CK1δ/CK1ε and pre-rRNA processing analysis

    PMID:24424021

    Open questions at the time
    • Whether RRP12 is a direct CK1 phosphosubstrate not established
    • Order of factor release not resolved
  5. 2014 High

    Showed Rrp12 acts not only in pre-40S export but also in earlier nucleolar 90S maturation, cooperating with Crm1 across both steps.

    Evidence Conditional depletion, Northern blot pre-rRNA processing, fluorescence microscopy, and genetic epistasis with crm1 mutants in yeast

    PMID:25474739

    Open questions at the time
    • Molecular nature of Rrp12-Crm1 cooperation at the 90S step unclear
    • Export cargo recognition mechanism not defined
  6. 2019 Medium

    Identified an r-protein assembly checkpoint: the S0-cluster at the subunit neck must be assembled to permit Rrp12 release from late SSU precursors.

    Evidence Semi-quantitative proteomics of Rio2-associated SSU precursors from r-protein deletion strains with biochemical co-precipitation in yeast

    PMID:30653518

    Open questions at the time
    • Structural basis of S0-cluster-dependent Rrp12 release not resolved
    • Single-lab study without orthogonal in vivo confirmation
  7. 2022 High

    Resolved the early 90S role: RRP12-ENP1 form a functional unit encircling the 18S 3' major domain, with Cms1 restraining their premature binding to allow ordered rRNA modification.

    Evidence Null-suppressor genetics, co-precipitation, cryo-EM of 90S particles, and rRNA processing assays in yeast

    PMID:36417864

    Open questions at the time
    • Trigger for RRP12-ENP1 stable engagement after Cms1 release not defined
    • Human conservation of the Cms1-regulated step untested
  8. 2015 Medium

    Connected human RRP12 to nucleolar stress signaling, showing it represses p53 stability to promote survival under cytotoxic stress.

    Evidence RRP12 overexpression and siRNA knockdown in U2OS cells with doxorubicin/actinomycin D treatment and p53 activity, apoptosis, and viability assays

    PMID:26499779

    Open questions at the time
    • No direct biochemical mechanism for p53 suppression established
    • Whether the effect requires RRP12's ribosome biogenesis function unknown
  9. 2021 Low

    Linked RRP12 upregulation to proliferation in early colorectal neoplasia.

    Evidence TMT quantitative proteomics of tissue and RRP12 knockdown in adenoma organoids with viability/proliferation assays

    PMID:34194496

    Open questions at the time
    • No molecular pathway placement beyond general proliferation
    • Single-lab organoid study without mechanistic readout
  10. 2023 Medium

    Extended the cancer role, showing RRP12 promotes migration, invasion, and metastasis through ZEB1-mediated EMT.

    Evidence RRP12 knockdown in CRC cell lines, migration/invasion assays, in vivo metastasis model, and EMT/ZEB1 Western blots

    PMID:37969827

    Open questions at the time
    • No direct biochemical interaction between RRP12 and ZEB1 demonstrated
    • Mechanism linking ribosome-biogenesis factor to ZEB1 regulation unknown
  11. 2025 Medium

    Established RRP12 as a human disease gene, with biallelic loss-of-function causing autosomal recessive brain calcifications linked to disrupted nucleolar function.

    Evidence Exome sequencing and homozygosity mapping, patient-fibroblast protein and nucleolar morphology analysis, and zebrafish rrp12 morpholino knockdown

    PMID:41059649

    Open questions at the time
    • Mechanism connecting ribosome biogenesis defect to brain calcification not defined
    • Morpholino phenotype lacks genetic rescue confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RRP12's conserved role in pre-40S biogenesis mechanistically gives rise to its human disease, p53, and EMT phenotypes remains unresolved.
  • No direct biochemical link established between RRP12 and p53 or ZEB1
  • Whether disease phenotypes arise from ribosome biogenesis loss versus non-ribosomal functions is unknown
  • No structural model of human RRP12 in pre-ribosomal particles

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005730 nucleolus 4 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-9609507 Protein localization 2
Partners
CMS1CRM1ENP1KAP121RIO2
Complex memberships
90S pre-ribosomepre-40S ribosomal particle

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 RRP12 is a component of pre-40S ribosomal subunit precursors. Inhibition or co-depletion of CK1δ and CK1ε results in failure to recycle RRP12 (along with other trans-acting factors including ENP1/BYSL, LTV1, DIM2/PNO1, RIO2, and NOB1) from pre-40S particles after nuclear export, demonstrating RRP12's role in late cytoplasmic 40S maturation steps. Tandem affinity purification of pre-40S particles, shRNA-mediated co-depletion of CK1δ/CK1ε, pre-rRNA processing analysis Journal of cell science High 24424021
2010 Human RRP12 (a HEAT-repeat nuclear protein) associates with late pre-40S ribosomal precursors. Upon loss of the pre-40S-associated kinase Rio2, increased levels of RRP12 are trapped on late 40S precursors, RRP12 is partially mislocalized to the cytoplasm, and fails to efficiently recycle back to the nucleus, placing RRP12 in the late cytoplasmic 40S maturation pathway downstream of Rio2. TAP purification of pre-40S particles combined with inducible shRNA-mediated depletion of Rio2; subcellular localization by immunofluorescence; proteomic identification of pre-40S components RNA (New York, N.Y.) High 21097556
2014 Yeast Rrp12 is required for the exit of pre-40S particles to the cytoplasm and for proper maturation dynamics of upstream 90S pre-ribosomes. In vivo elimination of Rrp12 leads to accumulation of nucleoplasmic 90S-to-pre-40S transitional particles, abnormal 35S pre-rRNA processing, delayed elimination of processing byproducts, and complete block of pre-40S export. The exportin Crm1 is required for the same pre-ribosome maturation events, indicating Rrp12 and Crm1 cooperate in both nuclear export and earlier nucleolar biosynthetic steps. Yeast genetics (conditional depletion), pre-rRNA processing analysis (Northern blot), fluorescence microscopy of pre-40S localization, genetic epistasis with crm1 mutants PLoS genetics High 25474739
2011 Yeast Rrp12 plays a ribosome-synthesis-independent role in cell cycle progression and the DNA damage response by participating in a karyopherin Kap121-dependent nuclear import route that is crucial for nuclear sequestration of ribonucleotide reductase subunits, thereby ensuring proper kinetics of deoxyribonucleotide production during the cell cycle. Rrp12 acts as a cofactor for the full functionality of Kap121 in this import route, mechanistically distinct from its role in ribosome biogenesis. Yeast functional screen, genetic epistasis, nuclear import assays, analysis of ribonucleotide reductase localization Molecular and cellular biology High 21482668
2008 Yeast Rrp12 (a HEAT-repeat/Armadillo-domain export factor) and the KH-domain protein DIM2 are both involved in the nucleocytoplasmic translocation of pre-40S ribosomes. Both are nucleolar-restricted (entrapped) upon nutritional, osmotic, and oxidative stress, and upon rapamycin treatment, establishing that the TOR signaling cascade controls their subcellular distribution and thereby regulates pre-40S ribosome export. Subcellular localization by fluorescence microscopy under stress/rapamycin treatment; pre-40S export assays; genetic analysis of TOR pathway control RNA (New York, N.Y.) High 18755838
2019 In yeast, the S0-cluster of ribosomal proteins (around rpS0/uS2) at the SSU 'neck' is specifically required for efficient release of the two nuclear export factors Rrp12 and Slx9 from late SSU precursors, and for correct incorporation of the late-acting biogenesis factor Rio2. Incomplete assembly of the S0-cluster specifically impairs Rrp12/Slx9 release, identifying an r-protein assembly checkpoint controlling Rrp12 dissociation. Semi-quantitative proteomics of affinity-purified Rio2-associated SSU precursors from r-protein deletion strains; complementary biochemical co-precipitation approaches PloS one Medium 30653518
2022 Cms1 was identified as a null suppressor of a nop14 mutant impaired in Rrp12-Enp1 factor recruitment to the 90S pre-ribosome. Cms1 associates with the 18S rRNA 3' major domain of an early 90S and restricts premature Rrp12-Enp1 binding to this domain, allowing snR83 to perform pseudouridylation modifications before subsequent 90S assembly steps coupled with Cms1 release occur. Thus, Rrp12-Enp1 are identified as a functional unit that encircles the 3' major domain in the mature 90S. Suppressor genetics (null suppressor screen), co-precipitation/affinity purification, cryo-EM structural analysis of 90S particles, rRNA processing assays Cell reports High 36417864
2015 In human osteosarcoma (U2OS) cells, RRP12 overexpression suppresses p53 stability and activity during cytotoxic stress (doxorubicin or actinomycin D-induced nucleolar disruption), whereas RRP12 silencing enhances p53 activity, cell cycle arrest, and apoptosis. This demonstrates that RRP12 promotes cell survival during nucleolar stress via repression of p53 stability. RRP12 overexpression and siRNA knockdown in U2OS cells; cytotoxic drug treatment; cell viability, apoptosis, and p53 activity assays Tumour biology Medium 26499779
2023 In colorectal cancer cells, knockdown of RRP12 suppresses cell migration and invasion, and reverses metastasis in vivo. RRP12 promotes the epithelial-mesenchymal transition (EMT) process in a ZEB1-mediated manner, as RRP12 knockdown reduces ZEB1 levels and alters EMT-related markers. RRP12 knockdown (siRNA/shRNA) in CRC cell lines; migration/invasion assays; in vivo metastasis model; Western blot for EMT markers and ZEB1; bioinformatic pathway analysis Journal of gastrointestinal oncology Medium 37969827
2025 Biallelic loss-of-function variants in RRP12 cause autosomal recessive brain calcifications in humans. Patient-derived fibroblasts show significant reduction in RRP12 protein levels and abnormal nucleolar morphology. In a zebrafish knockdown model, rrp12 loss causes severe developmental delay, crimping, and early lethality, consistent with an essential role in RNA metabolism. Exome sequencing and homozygosity mapping; Western blot and immunocytofluorescence on patient fibroblasts; rrp12 morpholino knockdown in zebrafish with phenotypic assessment Movement disorders Medium 41059649
2021 RRP12 knockdown in adenoma organoids impedes cell viability and proliferation, establishing a functional role for RRP12 in supporting proliferation in early colorectal neoplasia. RRP12 protein was identified as upregulated in the normal-to-adenoma transition by quantitative proteomics. TMT-based quantitative proteomics of tissue specimens; RRP12 knockdown in adenoma organoids with viability/proliferation assays Journal of oncology Low 34194496

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene 229 23318442
2017 Basal-like breast cancer: molecular profiles, clinical features and survival outcomes. BMC medical genomics 73 28351365
2014 Prostate cancer risk locus at 8q24 as a regulatory hub by physical interactions with multiple genomic loci across the genome. Human molecular genetics 49 25149474
2010 Tandem affinity purification combined with inducible shRNA expression as a tool to study the maturation of macromolecular assemblies. RNA (New York, N.Y.) 41 21097556
2014 CK1δ and CK1ε are components of human 40S subunit precursors required for cytoplasmic 40S maturation. Journal of cell science 38 24424021
2008 TOR regulates the subcellular distribution of DIM2, a KH domain protein required for cotranscriptional ribosome assembly and pre-40S ribosome export. RNA (New York, N.Y.) 38 18755838
2005 Separation of the Saccharomyces cerevisiae Paf1 complex from RNA polymerase II results in changes in its subnuclear localization. Eukaryotic cell 23 15643076
2019 POLR1B is upregulated and promotes cell proliferation in non-small cell lung cancer. Oncology letters 19 31897183
2014 Rrp12 and the Exportin Crm1 participate in late assembly events in the nucleolus during 40S ribosomal subunit biogenesis. PLoS genetics 19 25474739
2015 RRP12 is a crucial nucleolar protein that regulates p53 activity in osteosarcoma cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 26499779
2023 Identification of ZMYND19 as a novel biomarker of colorectal cancer: RNA-sequencing and machine learning analysis. Journal of cell communication and signaling 15 37428302
2017 A survey of proteomic biomarkers for heterotopic ossification in blood serum. Journal of orthopaedic surgery and research 13 28472996
2011 Ribosome synthesis-unrelated functions of the preribosomal factor Rrp12 in cell cycle progression and the DNA damage response. Molecular and cellular biology 13 21482668
2019 Impact of two neighbouring ribosomal protein clusters on biogenesis factor binding and assembly of yeast late small ribosomal subunit precursors. PloS one 11 30653518
2021 Exploration of the Key Proteins in the Normal-Adenoma-Carcinoma Sequence of Colorectal Cancer Evolution Using In-Depth Quantitative Proteomics. Journal of oncology 8 34194496
2013 Involvement of Schizosaccharomyces pombe rrp1+ and rrp2+ in the Srs2- and Swi5/Sfr1-dependent pathway in response to DNA damage and replication inhibition. Nucleic acids research 8 23828040
2023 A comprehensive protein interaction map and druggability investigation prioritized dengue virus NS1 protein as promising therapeutic candidate. PloS one 5 37498862
2023 RRP12 suppresses cell migration and invasion in colorectal cancer cell via regulation of epithelial-mesenchymal transition. Journal of gastrointestinal oncology 5 37969827
2025 RRP12 Variants Are Associated With Autosomal Recessive Brain Calcifications. Movement disorders : official journal of the Movement Disorder Society 3 41059649
2023 Using multi-tissue transcriptome-wide association study to identify candidate susceptibility genes for respiratory infectious diseases. Frontiers in genetics 3 37020999
2023 Identification of common genes and pathways underlying imatinib and nilotinib treatment in CML: a Bioinformatics Study. Nucleosides, nucleotides & nucleic acids 3 38117080
2022 Cms1 coordinates stepwise local 90S pre-ribosome assembly with timely snR83 release. Cell reports 3 36417864
2026 Multi-omics identification of a programmed cell death-related signature and potential target P4HB for bladder cancer based on a 101-combination machine learning and experimental validation. Clinical and experimental medicine 0 41925913
2026 LncRNA RRP12-AS regulates UCP1-mediated lipid metabolism through hnRNPA1 and the identification of a functionally conserved human homolog. The Journal of nutritional biochemistry 0 42248307

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