Affinage

C8ORF33

UPF0488 protein C8orf33 · UniProt Q9H7E9

Round 2 corrected
Length
229 aa
Mass
25.0 kDa
Annotated
2026-04-28
36 papers in source corpus 2 papers cited in narrative 2 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C8orf33 is a nucleolar protein recruited to DNA double-strand break (DSB) sites, where it promotes non-homologous end joining (NHEJ) by facilitating 53BP1 accumulation and antagonizing KAT8 acetyltransferase chromatin association, thereby reducing H4K16 acetylation and suppressing BRCA1/RAD51-mediated homologous recombination (PMID:41249114). C8orf33 deficiency leads to accelerated loss of ribosomal DNA repeats and increased cell death, indicating a role in safeguarding rDNA integrity (PMID:41249114). In hepatocellular carcinoma cells, C8orf33 knockdown reduces proliferation and tumorigenic capacity and downregulates the MIF signaling axis (MIF, CD74, CXCR4, CD44), correlating with decreased M2-like macrophage infiltration in xenograft models (PMID:41965457).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2025 High

    The molecular function of C8orf33 was unknown; chromatin profiling and DSB recruitment assays established that it localizes to the nucleolus, is recruited to DSB sites, and channels repair toward NHEJ by antagonizing KAT8-dependent H4K16 acetylation and promoting 53BP1 recruitment, thereby safeguarding rDNA repeat stability.

    Evidence siRNA/KO in human cells with 53BP1/BRCA1/RAD51 foci quantification, H4K16ac ChIP, DNA end resection assays, and rDNA repeat stability assays

    PMID:41249114

    Open questions at the time
    • Direct physical interaction between C8orf33 and KAT8 has not been demonstrated
    • Structural basis by which C8orf33 antagonizes KAT8 chromatin association is unknown
    • Whether C8orf33 plays additional roles in nucleolar functions beyond rDNA protection is unresolved
  2. 2026 Medium

    A role for C8orf33 in tumor cell biology was undefined; knockdown experiments in HCC cells revealed that C8orf33 supports proliferation, migration, and survival and sustains MIF-pathway signaling linked to immunomodulatory macrophage recruitment.

    Evidence siRNA knockdown in HCC cell lines with proliferation/apoptosis assays, subcutaneous xenograft models, scRNA-seq and spatial transcriptomics, qRT-PCR/western blot for MIF-axis components, IHC for macrophage markers

    PMID:41965457

    Open questions at the time
    • Mechanistic link between C8orf33 and MIF transcription/signaling is correlative and not directly tested
    • Whether the pro-tumorigenic phenotype reflects C8orf33's DSB repair function or an independent pathway is unclear
    • Single-laboratory study; independent validation in additional tumor models is lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether C8orf33 directly binds KAT8 or chromatin, its structural mechanism, and the relationship between its DSB repair and tumor-promoting functions remain unresolved.
  • No structural or biophysical characterization of C8orf33 exists
  • No direct binding partner has been biochemically validated
  • The contribution of NHEJ-promoting activity to rDNA maintenance versus general genome integrity is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-73894 DNA Repair 1
Partners
KAT8TP53BP1

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2025 C8orf33 is a nuclear protein that localizes predominantly to the nucleolus and is recruited to DNA double-strand break (DSB) sites in both nuclear and nucleolar regions. C8orf33 promotes recruitment of 53BP1 to DSB sites, thereby channeling DSB repair toward non-homologous end joining (NHEJ). Mechanistically, C8orf33 antagonizes chromatin association of the KAT8 acetyltransferase at DSB sites, leading to reduced histone H4 lysine 16 acetylation (H4K16ac) levels. Loss of C8orf33 enhances KAT8 chromatin binding, increases H4K16ac, promotes recruitment of HR factors BRCA1 and RAD51, and suppresses 53BP1 accumulation, thereby shifting DSB repair pathway choice from NHEJ toward homologous recombination (HR). C8orf33 deficiency causes accelerated loss of ribosomal DNA repeats and increased cell death, demonstrating its role in safeguarding genomic integrity. Chromatin profiling, immunofluorescence microscopy of DSB recruitment, loss-of-function (siRNA/KO) with readouts of 53BP1/BRCA1/RAD51 foci, H4K16ac ChIP, DNA end resection assays, rDNA repeat stability assay Cell death & disease High 41249114
2026 C8orf33 knockdown in HCC cell lines reduces proliferation, migration, and tumorigenic capacity, and increases apoptosis. C8orf33 loss is accompanied by reduced mRNA and protein levels of MIF and its receptor components (CD74, CXCR4, CD44), and in xenografts reduces infiltration of CD163/CD206-positive M2-like macrophages, suggesting C8orf33 contributes to a tumor-promoting MIF signaling axis linked to immunomodulatory macrophage recruitment. siRNA knockdown in HCC cell lines, in vitro proliferation/migration/apoptosis assays, subcutaneous xenograft models, scRNA-seq, spatial transcriptomics, cell-cell communication analysis, qRT-PCR and western blot for MIF-axis components, IHC for macrophage markers Discover oncology Medium 41965457

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2008 An empirical framework for binary interactome mapping. Nature methods 652 19060904
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2022 EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation. Nature communications 99 35013218
2020 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Molecular cell 88 32707033
2015 Interactions of the Antiviral Factor Interferon Gamma-Inducible Protein 16 (IFI16) Mediate Immune Signaling and Herpes Simplex Virus-1 Immunosuppression. Molecular & cellular proteomics : MCP 77 25693804
2019 STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production. Cell reports 71 31665637
2022 Scalable multiplex co-fractionation/mass spectrometry platform for accelerated protein interactome discovery. Nature communications 65 35831314
2018 RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer's disease. The Journal of biological chemistry 65 29802200
2015 Phospho-tyrosine dependent protein-protein interaction network. Molecular systems biology 61 25814554
2020 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D. Nature communications 60 31980649
2019 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. Nature communications 60 31515488
2022 Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy. Nature communications 53 36057605
2020 MAP4K Interactome Reveals STRN4 as a Key STRIPAK Complex Component in Hippo Pathway Regulation. Cell reports 51 32640226
2018 Characterizing ZC3H18, a Multi-domain Protein at the Interface of RNA Production and Destruction Decisions. Cell reports 47 29298432
2022 An mRNA expression-based signature for oncogene-induced replication-stress. Oncogene 37 35091678
2017 Deep sequencing and comprehensive expression analysis identifies several molecules potentially related to human poorly differentiated hepatocellular carcinoma. FEBS open bio 18 29123978
2023 Identifying Genetic Signatures Associated with Oncogene-Induced Replication Stress in Osteosarcoma and Screening for Potential Targeted Drugs. Biochemical genetics 8 37672187
2008 [Differentially expressed genes between upward and downward progressing types of nasopharyngeal carcinoma]. Ai zheng = Aizheng = Chinese journal of cancer 4 18479593
2025 C8orf33 dictates DNA double-strand break repair choice by modulating KAT8-mediated H4K16 acetylation. Cell death & disease 1 41249114
2026 Characterization and regulatory mechanism evaluation of C8orf33 in hepatocellular carcinoma through multiomics profiling. Discover oncology 0 41965457