Affinage

ENDOD1

Endonuclease domain-containing 1 protein · UniProt O94919

Length
500 aa
Mass
55.0 kDa
Annotated
2026-06-09
18 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ENDOD1 (also called NUMEN) is a transmembrane nuclease of the DNA/RNA non-specific nuclease family that acts in the repair of DNA double-strand breaks at the nuclear periphery (PMID:37322289). It carries intrinsic endonuclease and 3'→5' exonuclease activities that generate short 5' overhangs, operating as a downstream effector of DNA-PKcs to drive non-homologous end joining at heterochromatic lamina-associated domain breaks and deprotected telomeres (PMID:37322289). ENDOD1 is enriched in the nucleus following oxidative stress, and its loss is synthetic lethal both with homologous recombination deficiency, producing accumulation of double-strand breaks, and with TP53 mutation, producing rapid single-stranded DNA accumulation and cell death (PMID:35606358). Beyond its repair role, ENDOD1 co-assembles with the ER-membrane E3 ligase RNF26 together with TMEM43, TMEM33, and TMED1 to modulate innate immune signalling through the cGAS-STING pathway (PMID:32614325), and its expression restrains proliferation, migration, and invasion in cancer cells (PMID:28532481). Recombinant nuclease activity confirmed in a fish ortholog, where it is induced upon bacterial challenge, supports the conserved catalytic identity of the protein (PMID:26784919).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2016 Medium

    Established that ENDOD1 is a bona fide nuclease, answering whether the protein possesses intrinsic catalytic activity and linking it to immune-responsive contexts.

    Evidence Recombinant Japanese flounder ENDOD1 expressed in E. coli with in vitro DNase assays and tissue DNase measurement after bacterial injection

    PMID:26784919

    Open questions at the time
    • Demonstrated in a fish ortholog, not in a mammalian system
    • Does not define substrate specificity (endo vs exo) or directionality
    • No link to a specific cellular pathway
  2. 2017 Medium

    Showed that ENDOD1 acts as a growth-suppressive factor in cancer, raising the question of how a nuclease constrains proliferation and motility.

    Evidence Bidirectional overexpression and siRNA knockdown in prostate cancer cell lines with proliferation, cell-cycle, and migration/invasion assays

    PMID:28532481

    Open questions at the time
    • Molecular mechanism linking nuclease activity to G0/G1 arrest not defined
    • No connection to DNA repair pathway established at this stage
    • Single lineage (prostate) tested
  3. 2020 Medium

    Identified an ER-membrane complex containing ENDOD1, revealing a role distinct from nuclear DNA processing in innate immune regulation.

    Evidence Proteomic interaction mapping and Co-IP of RNF26 with TMEM43, TMEM33, TMED1, plus cGAS-STING innate immune signalling assays

    PMID:32614325

    Open questions at the time
    • Direct vs indirect membership of ENDOD1 in the complex not resolved
    • Whether nuclease activity is required for immune modulation unknown
    • Single-lab interaction dataset
  4. 2022 High

    Defined ENDOD1 as a DNA-repair factor whose loss creates synthetic lethal vulnerabilities, establishing therapeutic relevance in HR-deficient and TP53-mutant tumors.

    Evidence Knockout cell lines, chromatin-association fractionation (PARP), H2O2-induced nuclear localization imaging, siRNA, and xenograft models

    PMID:35606358

    Open questions at the time
    • Catalytic mechanism underlying the repair role not biochemically dissected here
    • Pathway step at which ENDOD1 acts left unspecified
    • Relationship between nuclear enrichment signal and damage type unclear
  5. 2023 High

    Resolved the molecular mechanism: ENDOD1/NUMEN generates short 5' overhangs via endo- and exonuclease activities to enable DNA-PKcs-dependent NHEJ at the nuclear periphery.

    Evidence Genome-wide synthetic viability CRISPR screen, in vitro nuclease assays, nuclear periphery localization, genetic epistasis with DNA-PKcs in BRCA1-deficient cells

    PMID:37322289

    Open questions at the time
    • Structural basis of overhang generation not determined
    • How its transmembrane topology is reconciled with nuclear-periphery DNA access is unresolved
    • Mechanistic relationship between the repair and cGAS-STING roles not connected

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ENDOD1's nuclease-driven DNA repair function mechanistically intersects with its ER-membrane cGAS-STING role and its growth-suppressive activity remains unresolved.
  • No unifying model linking nuclear repair and ER-membrane immune signalling
  • No structural model of the catalytic mechanism
  • Recruitment to and topology at the nuclear periphery undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 2 GO:0140097 catalytic activity, acting on DNA 2
Localization
GO:0005634 nucleus 1 GO:0005635 nuclear envelope 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-73894 DNA Repair 2
Partners
PRKDCRNF26TMED1TMEM33TMEM43
Complex memberships
RNF26-TMEM43-TMEM33-TMED1 ER-membrane complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 ENDOD1 (renamed NUMEN) is a transmembrane nuclease that generates short 5' overhangs through its endonuclease and 3'→5' exonuclease activities, facilitating non-homologous end joining (NHEJ)-dependent repair of double-stranded DNA breaks at the nuclear periphery, including heterochromatic lamina-associated domain breaks and deprotected telomeres. It functions as a downstream effector of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Genome-wide synthetic viability CRISPR-Cas9 screen, in vitro nuclease activity assays, nuclear periphery localization experiments, genetic epistasis with DNA-PKcs, BRCA1-deficient breast cancer cell models Nature cell biology High 37322289
2022 ENDOD1 functions in DNA repair: it is enriched in the nucleus following H2O2-induced oxidative stress, and ENDOD1-knockout cells show increased PARP chromatin-association. Loss of ENDOD1 is synthetic lethal with homologous recombination defects, causing accumulation of DNA double-strand breaks. Additionally, ENDOD1 depletion in TP53-mutated tumor cells results in rapid single-stranded DNA accumulation and cell death, revealing a synthetic lethality between ENDOD1 and p53. ENDOD1 knockout cell lines, cellular fractionation/chromatin association assays (PARP), H2O2 treatment with nuclear localization imaging, siRNA knockdown, xenograft tumor models with siRNA knockdown Nature communications High 35606358
2020 ENDOD1 co-assembles with RNF26, TMEM43, TMEM33, and TMED1 at the ER membrane to form a complex capable of modulating innate immune signalling through the cGAS-STING pathway. Comparative proteomic workflow (protein-protein interaction mapping by MS), Co-immunoprecipitation of ER-localized E3 ubiquitin ligase RNF26 and its interactors, functional innate immune signalling assays eLife Medium 32614325
2016 Recombinant ENDOD1 protein from Japanese flounder (Paralichthys olivaceus, Jf_ENDOD1) produced in E. coli displays DNase (endonuclease) activity in vitro, consistent with its classification as a member of the DNA/RNA non-specific nucleases family. DNase activity in kidney and spleen extracts was elevated after bacterial challenge, correlating with ENDOD1 upregulation. Recombinant protein expression in E. coli, in vitro DNase activity assay, tissue DNase activity measurement after bacterial injection Fish & shellfish immunology Medium 26784919
2017 In prostate cancer cells, overexpression of ENDOD1 suppresses cell proliferation, induces G0/G1 cell cycle arrest, and inhibits cell migration and invasion; conversely, siRNA-mediated silencing of ENDOD1 promotes cell proliferation, migration, and invasion. No apoptotic effects were observed upon ENDOD1 manipulation. Overexpression and siRNA knockdown in PCa cell lines, MTT proliferation assay, flow cytometry cell cycle analysis, Transwell migration and invasion assays BMC cancer Medium 28532481

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Towards complete analysis of the platelet proteome. Proteomics 144 11921445
2020 Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling. eLife 71 32614325
2011 Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. Pharmacogenomics 50 21332311
2011 Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines. PloS one 43 21829708
2018 Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre-miR-148a on gene regulation. Cancer science 42 29660218
2010 Identification of genes associated with local aggressiveness and metastatic behavior in soft tissue tumors. Translational oncology 42 20165692
2020 Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes. Cancers 37 32977589
2008 Effect of astrocyte-targeted production of IL-6 on traumatic brain injury and its impact on the cortical transcriptome. Developmental neurobiology 30 18000830
2023 Integrated bioinformatics approaches to investigate alterations in transcriptomic profiles of monkeypox infected human cell line model. Journal of infection and public health 22 37992435
2023 Transmembrane nuclease NUMEN/ENDOD1 regulates DNA repair pathway choice at the nuclear periphery. Nature cell biology 20 37322289
2023 Malignant undifferentiated epithelioid neoplasms with MAML2 rearrangements: A clinicopathologic study of seven cases demonstrating a heterogenous entity. Genes, chromosomes & cancer 18 36344258
2020 Role of miR-30a-3p Regulation of Oncogenic Targets in Pancreatic Ductal Adenocarcinoma Pathogenesis. International journal of molecular sciences 17 32899691
2022 Synthetic lethality between TP53 and ENDOD1. Nature communications 11 35606358
2017 Identification of endonuclease domain-containing 1 as a novel tumor suppressor in prostate cancer. BMC cancer 11 28532481
2021 Mapping of the amniotic fluid proteome of fetuses with congenital anomalies of the kidney and urinary tract identifies plastin 3 as a protein involved in glomerular integrity. The Journal of pathology 8 33987838
2016 Identification of endonuclease domain-containing 1 gene in Japanese flounder Paralichthys olivaceus. Fish & shellfish immunology 5 26784919
2026 Brain Proteomic Responses to Glucocorticoids and Their Relationship With Transcriptome: A Systematic Meta-Analysis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41996197
2025 Uncovering the Molecular Networks of Extracellular Vesicles in the Pathogenesis of Periodontitis. International dental journal 0 41138693

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