Affinage

DDIAS

DNA damage-induced apoptosis suppressor protein · UniProt Q8IXT1

Length
998 aa
Mass
111.6 kDa
Annotated
2026-06-09
16 papers in source corpus 13 papers cited in narrative 14 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

DDIAS (hNoxin/C11orf82) is a stress- and oncogene-induced nuclear protein that functions as a multifunctional anti-apoptotic and pro-survival factor in cancer cells (PMID:17515607, PMID:24214091). It is transcriptionally driven by stress and growth-factor signaling: NFATc1 binds the DDIAS promoter to confer cisplatin resistance (PMID:26493727), and EGF-activated ERK5/MEF2B induces DDIAS to promote invasion via post-translational β-catenin stabilization (PMID:27412911); upstream, JNK activation blocks NFATc1 nuclear translocation to repress DDIAS (PMID:33859351). Its protein level is controlled by an HSP70/CHIP axis, in which HSP70-bound DDIAS is recruited to the E3 ligase CHIP through its TPR domain and ubiquitinated by the CHIP U-box domain for proteasomal degradation (PMID:28079882), while its mRNA is stabilized by NAT10-mediated ac4C modification feeding into PI3K/AKT signaling (PMID:40389420). Mechanistically, DDIAS suppresses TRAIL-induced apoptosis by binding the death effector domain of FADD to block DISC assembly and by promoting RSK2-mediated caspase-8 degradation (PMID:29242605), and it sustains oncogenic STAT3 signaling by binding the STAT3 transactivation domain to competitively exclude the phosphatase PTPRM and preserve Y705 phosphorylation (PMID:31900385). DDIAS also operates in DNA metabolism, acting as a cofactor of the DNA polymerase α–primase complex to accelerate G1-S transition (PMID:25612832) and, as a single-stranded-DNA-binding effector of the mitotic TOPBP1–CIP2A complex, suppressing ssDNA accumulation to maintain genome integrity, with synthetic lethality in BRCA1/BRCA2-deficient cells.

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 Medium

    Established that the DDIAS ortholog Noxin is a stress-inducible nuclear protein that opposes apoptosis and arrests the cell cycle independently of p53, defining its baseline role as a pro-survival stress effector.

    Evidence Knockout mouse model, ectopic overexpression, and cell cycle analysis under genotoxic/oxidative stress

    PMID:17515607

    Open questions at the time
    • No molecular partners identified
    • Mechanism of G1 arrest undefined
    • Human ortholog function not yet tested
  2. 2013 Medium

    Showed that human DDIAS is anti-apoptotic in NSCLC, with knockdown triggering p38 MAPK/p53-mediated apoptosis, transferring the mouse phenotype to a human cancer context.

    Evidence siRNA knockdown, comet assay, western blot, and shRNA xenograft in A549 cells

    PMID:24214091

    Open questions at the time
    • DNA-binding C-domain function not biochemically dissected
    • Direct apoptotic targets not identified
  3. 2015 Medium

    Identified the transcriptional input NFATc1 and a DNA-replication function, linking DDIAS expression to chemoresistance and proliferation.

    Evidence NFATc1 promoter ChIP/binding plus caspase rescue (cisplatin); Co-IP with DNA polymerase α and cell cycle assays in HCC

    PMID:25612832 PMID:26493727

    Open questions at the time
    • DDIAS–polymerase α interaction rests on single Co-IP
    • Direct role in DNA synthesis vs. indirect effect unresolved
  4. 2016 Medium

    Defined a second transcriptional axis (EGF→ERK5/MEF2B) and a pro-invasive output through post-translational β-catenin stabilization.

    Evidence MEF2B ChIP at DDIAS promoter, CA-MEK5/ERK5 inhibition, MEF2B siRNA, invasion assays

    PMID:27412911

    Open questions at the time
    • Mechanism of β-catenin stabilization not biochemically defined
    • No direct DDIAS–β-catenin interaction shown
  5. 2017 High

    Resolved how DDIAS protein levels are controlled and how it directly blocks death-receptor apoptosis, providing concrete biochemical mechanisms.

    Evidence Y2H/Co-IP/ubiquitination with HSP70-CHIP; reciprocal Co-IP mapping DDIAS N-terminus to FADD DED, DISC assays, RSK2/caspase-8 degradation; p38-ATF2 proliferation pathway

    PMID:28079882 PMID:28618963 PMID:29242605

    Open questions at the time
    • Stoichiometry of DDIAS within the DISC unclear
    • Whether FADD-blocking and RSK2 arms are coupled is unknown
  6. 2020 High

    Established a direct mechanism by which DDIAS sustains STAT3 signaling, identifying it as a competitor of the STAT3 phosphatase PTPRM.

    Evidence siRNA PTP library screen, domain Co-IP (DDIAS–STAT3 TAD; PTPRM–STAT3), Y705F mutant, IL-6 stimulation

    PMID:31900385

    Open questions at the time
    • Structural basis of TAD competition not determined
    • Whether competition occurs in nucleus or cytoplasm unclear
  7. 2021 Medium

    Placed JNK upstream of the NFATc1→DDIAS axis and demonstrated DDIAS transcription as a druggable node via DGG-100629.

    Evidence Chemical screen, JNK1 siRNA/SP600125 epistasis, NFATc1 translocation assay, DDIAS/STAT3 rescue, xenograft

    PMID:33859351

    Open questions at the time
    • Direct molecular target of DGG-100629 not identified
    • JNK–NFATc1 connection not biochemically mapped
  8. 2025 Medium

    Added mRNA-level regulation by NAT10-mediated ac4C and reinforced β-catenin/STAT3 outputs in additional disease contexts.

    Evidence AcRIP-seq, NAT10 knockdown/DDIAS rescue (PI3K/AKT); β-catenin rescue in endometrial cancer; STAT3 agonist rescue in Kawasaki endothelial model

    PMID:39293834 PMID:40389420 PMID:41052043

    Open questions at the time
    • β-catenin and STAT3 disease-context studies are single-siRNA with no direct interaction
    • Functional consequence of specific ac4C sites untested
  9. 2025 High

    Recast DDIAS as a phosphorylation-dependent ssDNA-binding effector of the mitotic TOPBP1-CIP2A complex that protects genome integrity and is synthetic lethal with BRCA1/BRCA2 loss.

    Evidence Interactome/PLA (DDIAS–TOPBP1), ssDNA-binding assay, domain mutants, BRCA1/BRCA2 synthetic lethality and DNA polymerase delta genetics (preprint)

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Phosphosites controlling complex assembly not fully mapped
    • Reconciliation of mitotic genome-integrity role with cytoplasmic apoptosis roles unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DDIAS coordinates its distinct nuclear genome-protection role with its cytoplasmic anti-apoptotic and STAT3/β-catenin signaling functions remains unresolved.
  • No structural model of DDIAS domains
  • Spatiotemporal partitioning of functions unknown
  • Whether ssDNA-binding underlies all roles untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-162582 Signal Transduction 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
FADDHSPA1APOLA1PTPRMSTAT3STUB1TOPBP1
Complex memberships
DNA polymerase alpha-primase complexTOPBP1-CIP2A complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Noxin (mouse ortholog of DDIAS) accumulates in the nucleus in response to stress signals (gamma/UV irradiation, hydrogen peroxide, adriamycin, cytokines), and ectopic expression arrests the cell cycle at G1 independently of p53 activity. Loss of Noxin leads to increased cell death, suggesting it opposes apoptosis downstream of stress-induced p53. Knockout mouse model, ectopic overexpression, cell cycle analysis Molecular and cellular biology Medium 17515607
2013 Human Noxin (hNoxin/DDIAS) contains a DNA-binding C-domain in RPA1 and functions as an anti-apoptotic protein in response to DNA damage; knockdown activates p38 MAPK/p53-mediated apoptosis in A549 NSCLC cells, while overexpression rescues cells from DNA damage-induced apoptosis. siRNA knockdown, comet assay, western blot (p38/p53 activation), adenoviral shRNA xenograft International journal of cancer Medium 24214091
2015 NFATc1 transcriptionally activates DDIAS by binding to NFAT consensus sequences in the DDIAS promoter, and DDIAS expression contributes to cisplatin resistance in lung cancer cells; DDIAS overexpression rescues cells from cisplatin-mediated death and caspase-3/7 activation. DDIAS promoter analysis, NFATc1 ChIP/binding assay, siRNA knockdown, overexpression rescue, caspase-3/7 assay Biochimica et biophysica acta Medium 26493727
2015 NOXIN/DDIAS interacts with DNA polymerase α, functioning as a cofactor of the DNA polymerase-primase complex to promote DNA synthesis and accelerate G1-S phase transition in hepatocellular carcinoma cells. Co-immunoprecipitation (NOXIN–DNA polymerase α interaction), cell cycle analysis, overexpression/knockdown proliferation assays International journal of cancer Medium 25612832
2016 EGF activates the ERK5/MEF2B pathway to induce DDIAS transcription; MEF2B binds a MEF2 site in the DDIAS promoter (by ChIP), and DDIAS in turn promotes invasion by increasing β-catenin expression at the post-translational level. Chromatin immunoprecipitation (MEF2B at DDIAS promoter), CA-MEK5 overexpression, pharmacological ERK5 inhibition, MEF2B siRNA, invasion assay, western blot (β-catenin) Biochimica et biophysica acta Medium 27412911
2017 DDIAS stability is regulated by the E3 U-box ubiquitin ligase CHIP (carboxyl terminus of HSP70-interacting protein) via proteasomal degradation; CHIP physically associates with both the N- and C-terminal regions of DDIAS, and HSP70-bound DDIAS is recruited to CHIP via its TPR domain. The CHIP U-box domain is required for DDIAS ubiquitination. Yeast two-hybrid screening (CHIP isolation), Co-IP (CHIP–DDIAS), ubiquitination assay, domain mutant analysis (TPR, U-box), half-life measurement Cell death & disease High 28079882
2017 DDIAS suppresses TRAIL-induced apoptosis by two mechanisms: (1) the N-terminus of DDIAS binds the death effector domain of FADD and prevents FADD recruitment to the DISC, blocking caspase-8 activation; (2) DDIAS promotes EGF-induced RSK2 phosphorylation, which leads to caspase-8 ubiquitination and proteasomal degradation. Co-IP (DDIAS N-terminus–FADD DED), DISC assembly assay, caspase-8 ubiquitination/proteasome assay, RSK2 overexpression rescue, siRNA knockdown Oncogene High 29242605
2017 Noxin/DDIAS promotes breast cancer cell proliferation via the P38-ATF2 signaling pathway; Noxin overexpression increases phospho-P38 and phospho-ATF2 levels and upregulates Cyclin D1 and Cyclin E1, and these effects are reversed by a P38 inhibitor. Overexpression/siRNA knockdown, western blot (p-P38, p-ATF2, Cyclin D1, Cyclin E1), P38 inhibitor pharmacological rescue Tumour biology Medium 28618963
2020 DDIAS promotes STAT3 Y705 phosphorylation by binding to the STAT3 transactivation domain (TAD) and thereby competing with the phosphatase PTPRM to prevent PTPRM-mediated dephosphorylation of STAT3; PTPRM was identified as a novel STAT3 phosphatase via siRNA PTP library screening. siRNA PTP library screen (PTPRM identification), Co-IP (DDIAS–STAT3 TAD; PTPRM–STAT3), Y705F STAT3 mutant, PTPRM overexpression/knockdown, IL-6 stimulation, western blot (pY705-STAT3) Oncogenesis High 31900385
2021 The small molecule DGG-100629 inhibits DDIAS transcription by activating JNK and blocking NFATc1 nuclear translocation; JNK1 knockdown or JNK inhibitor SP600125 restores DDIAS expression and reverses DGG-100629-induced cell death, placing JNK upstream of NFATc1/DDIAS. Chemical library screen, JNK1 siRNA/pharmacological inhibitor (SP600125), NFATc1 nuclear translocation assay, DDIAS/STAT3 overexpression rescue, xenograft Experimental & molecular medicine Medium 33859351
2025 NAT10-mediated ac4C modification stabilizes DDIAS mRNA; decreased NAT10 levels reduce DDIAS mRNA stability, and ectopic DDIAS expression rescues the anti-proliferative/anti-invasive effects of NAT10 knockdown by modulating the PI3K/AKT pathway. AcRIP-seq (ac4C site identification on DDIAS mRNA), NAT10 knockdown, DDIAS overexpression rescue, western blot (PI3K/AKT) Scientific reports Medium 40389420
2025 DDIAS is a phosphorylation-dependent component of the TOPBP1-CIP2A complex during mitosis; DDIAS directly binds TOPBP1 and possesses single-stranded DNA (ssDNA)-binding activity. Disruption of the DDIAS–TOPBP1 interaction or inactivation of DDIAS ssDNA-binding ability impairs genome integrity and causes synthetic lethality with BRCA1/BRCA2 deficiency. DDIAS suppresses ssDNA during mitosis rather than promoting end-tethering. Proximity ligation/interactome (DDIAS–TOPBP1 direct interaction), ssDNA-binding assay, domain mutant disruption, synthetic lethality screen (BRCA1/BRCA2 double mutant), genetic interaction with DNA polymerase delta bioRxivpreprint High
2025 DDIAS knockdown in endometrial cancer cells suppresses β-catenin and its downstream targets (c-Myc, Cyclin D1, survivin) and inhibits EMT; these effects are rescued by β-catenin overexpression, establishing DDIAS as an upstream regulator of β-catenin in this context. siRNA knockdown, western blot (β-catenin pathway), β-catenin rescue overexpression, proliferation/migration/invasion assays PloS one Low 41052043
2024 In a Kawasaki disease endothelial cell model, DDIAS knockdown reduces p-STAT3 and CCL2 expression, and decreases M1 macrophage polarization; STAT3 agonist reverses the DDIAS knockdown effects, placing DDIAS upstream of STAT3/CCL2 in this inflammatory context. siRNA knockdown (si-DDIAS), western blot (p-STAT3, CCL2), ELISA (cytokines), flow cytometry (CD86 M1 marker), STAT3 agonist rescue Annals of clinical and laboratory science Low 39293834

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells. Oncogenesis 36 31900385
2015 DNA damage-induced apoptosis suppressor (DDIAS), a novel target of NFATc1, is associated with cisplatin resistance in lung cancer. Biochimica et biophysica acta 36 26493727
2013 Human Noxin is an anti-apoptotic protein in response to DNA damage of A549 non-small cell lung carcinoma. International journal of cancer 32 24214091
2016 DNA damage induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes β-catenin-mediated invasion. Biochimica et biophysica acta 29 27412911
2017 DDIAS suppresses TRAIL-mediated apoptosis by inhibiting DISC formation and destabilizing caspase-8 in cancer cells. Oncogene 25 29242605
2017 Stability of the cancer target DDIAS is regulated by the CHIP/HSP70 pathway in lung cancer cells. Cell death & disease 24 28079882
2015 NOXIN as a cofactor of DNA polymerase-primase complex could promote hepatocellular carcinoma. International journal of cancer 17 25612832
2007 noxin, a novel stress-induced gene involved in cell cycle and apoptosis. Molecular and cellular biology 16 17515607
2023 Expression of DR4, DR5, FAS, Caspase-8 and, DDIAS Genes in AML Patients. Medical journal of the Islamic Republic of Iran 12 37575689
2017 Noxin promotes proliferation of breast cancer cells via P38-ATF2 signaling pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 28618963
2023 DDIAS, DNA damage-induced apoptosis suppressor, is a potential therapeutic target in cancer. Experimental & molecular medicine 10 37121974
2021 DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway. Experimental & molecular medicine 6 33859351
2025 NAT10 promotes hepatocellular carcinoma progression by modulating the ac4C-DDIAS-PI3K-Akt axis. Scientific reports 3 40389420
2024 DDIAS Regulation of STAT3/CCL2 Promotes Macrophage Polarization to M1 type in Kawasaki Disease. Annals of clinical and laboratory science 1 39293834
2016 Data on the transcriptional regulation of DNA damage induced apoptosis suppressor (DDIAS) by ERK5/MEF2B pathway in lung cancer cells. Data in brief 1 27660814
2025 DDIAS promotes endometrial cancer progression via β-catenin signaling. PloS one 0 41052043

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