DNA damage response (DDR) pathway

The DNA damage response is the cellular surveillance system that detects DNA lesions, signals their presence, and orchestrates one of four outcomes: faithful repair, checkpoint-arrested repair, permanent senescence, or apoptosis. It is the convergence point for the genomic-instability hallmark of aging — progressive accumulation of unrepaired lesions is both a driver and a consequence of aging tissue dysfunction.

The DDR is not a single linear pathway but a web of parallel sensing-transduction-effector modules that respond to distinct lesion types ¹. Its central logic is three-tiered: sensors detect lesions; transducer kinases amplify the signal; effectors execute the cellular response. For the downstream transcriptional programs that p53 executes, see p53-pathway.

Canonical pathway IDs: KEGG hsa03450 (NHEJ) · hsa03440 (HR) · hsa03430 (MMR) · hsa04115 (p53 signaling) · Reactome R-HSA-73894 (DNA Repair) · R-HSA-5693606 (DNA Double-Strand Break Repair) · R-HSA-69473 (G2/M DNA damage checkpoint) · WikiPathways WP707 (DNA damage response).

Lesion types and the sensors that detect them

Lesion type	Major cause(s)	Primary sensor(s)	Transducer
Double-strand break (DSB)	Ionising radiation, replication-fork collapse, reactive oxygen species, V(D)J / class-switch recombination	MRN complex (MRE11–RAD50–NBN)	atm
Single-stranded DNA (ssDNA) / replication fork stalling	UV, replication stress, nucleotide depletion, hydroxyurea	RPA (coats exposed ssDNA) → ATRIP	ATR
Single-strand break (SSB) / base damage	Reactive oxygen species, alkylating agents, spontaneous depurination	PARP1, AP endonuclease (APE1)	PARP / ATR
Bulky adducts (helix-distorting)	UV-B, polycyclic aromatic hydrocarbons	XPC–RAD23B (global NER) / RNA Pol II stalling (TC-NER)	ATR
Mismatched bases	Replication errors	MutSα (MSH2–MSH6), MutLα (MLH1–PMS2)	ATR (after resection)

MRN complex: the DSB sensor

The MRN complex (MRE11–RAD50–NBN/NBS1) is the first responder to double-strand breaks ¹. It is recruited within seconds of DSB formation, before any amplification signal exists:

MRE11 — nuclease that generates the initial 3′-ssDNA overhang by resecting DSB ends (endo- and exonuclease activity). Mutations cause Nijmegen breakage syndrome-like disorder (ATLD).
RAD50 — coiled-coil ATPase with a hook domain; tethers broken DNA ends; may bridge sister chromatids.
NBN (NBS1) — regulatory/scaffolding subunit; recruits atm to DSBs via direct interaction; mutations cause Nijmegen breakage syndrome (NBS).

MRN activates atm allosterically: MRN-bound atm dimers autophosphorylate at Ser1981 and monomerise → activated monomers phosphorylate DDR substrates ².

RPA → ATRIP → ATR: the ssDNA sensor

Single-stranded DNA coated by RPA (Replication Protein A, the heterotrimeric ssDNA-binding protein) recruits ATRIP (ATR-Interacting Protein) ³. ATRIP forms a stable complex with ATR and targets it to RPA-ssDNA:

ssDNA (exposed at stalled fork or resected DSB) → RPA binding → ATRIP–ATR recruitment
→ ATR activation (also requires TopBP1 / ETAA1 co-activators) → CHK1 phosphorylation

This places ATR downstream of both primary replication stress AND secondary DSB processing (because DSB resection generates ssDNA, feeding both the ATM and ATR pathways in S phase).

PARP1: SSB sensor and first responder

PARP1 (Poly-ADP-ribose polymerase 1) binds SSBs with high affinity within milliseconds of formation and synthesises PAR chains (poly-ADP-ribose) on itself and surrounding chromatin, providing a scaffold for repair factors ⁴. In SSB repair:

PARP1 activation → XRCC1 recruitment → DNA ligase III → ligation (short-patch BER)
PARP1 is also activated by DSBs and replication gaps; its inhibition (PARP inhibitors, PARPi) in BRCA1/2-deficient cells kills cells via synthetic lethality (conversion of SSBs into DSBs at the replication fork)

Transducer kinases

All three major DDR kinases belong to the PIKK (phosphatidylinositol 3-kinase–like kinase) family and phosphorylate S/TQ motifs. They share substrates but have distinct sensory inputs.

ATM — the DSB kinase

atm (Ataxia-Telangiectasia Mutated) is the primary transducer for double-strand breaks ². It phosphorylates hundreds of substrates, including:

H2AX at Ser139 (γH2AX) — spreading 1–2 Mb from the DSB; marks the repair domain
CHK2 at Thr68 — amplifying checkpoint signal; CHK2 phosphorylates p53 (Ser20) and CDC25A/C
p53 at Ser15 — direct stabilisation (also phosphorylated by ATR and DNA-PK)
BRCA1, MDC1, 53BP1 — mediator recruitment and signal amplification
RAD51, PALB2 — HR initiation in S/G2

Loss-of-function mutations in ATM cause ataxia-telangiectasia (A-T): cerebellar degeneration, radiosensitivity, immunodeficiency, ~100-fold increased cancer risk — confirming ATM as a non-redundant DSB transducer in humans. See the atm protein page for detailed kinase domain structure and substrate list.

ATR — the replication stress kinase

ATR (ATM- and Rad3-related) is activated by RPA-ssDNA and is essential for S-phase viability (ATR knockout is embryonic lethal, unlike Atm−/− mice which are viable) ⁴. Key substrates:

CHK1 at Ser317/345 — the primary ATR effector checkpoint kinase; phosphorylates CDC25A (degradation) and CDC25C (cytoplasmic sequestration) → CDK1/2 inhibition → S and G2/M checkpoint
RPA32 at Ser33 — modulates RPA binding dynamics
H2AX — contributes to γH2AX at stalled forks
RAD51, FANCD2 — HR and Fanconi anemia pathway activation

ATR → CHK1 → CDC25 forms the canonical intra-S and G2/M checkpoint axis that prevents mitotic entry with under-replicated or damaged DNA.

DNA-PK — the NHEJ kinase

DNA-PK (DNA-dependent protein kinase; catalytic subunit DNA-PKcs, encoded by PRKDC) is activated by the Ku70–Ku80 heterodimer that binds directly to DNA ends at DSBs. DNA-PK drives NHEJ (non-homologous end-joining) and also contributes to DDR signaling ⁴:

Phosphorylates H2AX (Ser139) — contributes to γH2AX along with ATM and ATR
Autophosphorylates at multiple sites — regulates end-processing by Artemis and DNA ligase IV–XRCC4–XLF
Phosphorylates p53 at Ser15 — minor role compared to ATM

Ku heterodimer binding to DNA ends is the first committed step toward NHEJ. Loss of PRKDC causes severe combined immunodeficiency (SCID) in mice (due to failure of V(D)J recombination, which requires NHEJ).

Mediators and signal amplifiers

Mediators propagate and amplify the primary kinase signal into megabase-scale chromatin domains, enabling multiple repair-factor concentrations at the DSB.

γH2AX: the DSB chromatin mark

ATM (and ATR/DNA-PK) phosphorylates histone H2AX at Ser139, producing γH2AX — which spreads outward from the break over 1–2 Mb of chromatin within minutes ⁵. γH2AX foci are:

A quantitative readout of DSB number — used experimentally as a biomarker (immunofluorescence)
A scaffold for MDC1, which binds γH2AX via its BRCT domain and recruits the MRN complex in a secondary wave, amplifying ATM activation

γH2AX foci accumulate progressively with organismal age in multiple tissues, including brain, liver, and lymphocytes — making γH2AX a proposed biomarker of age-related genomic instability ⁶.

MDC1 (Mediator of DNA damage checkpoint 1)

MDC1 binds γH2AX (BRCT domain) and then recruits ubiquitin ligases RNF8 and RNF168 → H2A-K13/K15 ubiquitination → creates a two-tier chromatin mark recognized by 53BP1 and BRCA1 in an antagonistic fashion that determines repair pathway choice.

53BP1 and BRCA1: the repair pathway switch

The competition between 53BP1 (p53-binding protein 1) and BRCA1 at ubiquitinated chromatin is the dominant mechanism of repair pathway choice between NHEJ and HR:

Factor	Effect	Outcome
53BP1 (with RIF1, PTIP)	Blocks DNA-end resection	Promotes NHEJ; active in G1
BRCA1 (with CtIP, MRN)	Promotes long-range DSB resection (5′→3′)	Promotes HR; active in S/G2

Cell-cycle phase determines the balance: 53BP1-mediated NHEJ dominates in G1 (no sister chromatid); BRCA1-mediated HR dominates in S/G2 (sister chromatid available) ⁴.

Nuclear cGAS: an intra-nuclear brake on HR

cgas (cyclic GMP-AMP synthase) was canonically known as a cytosolic DNA sensor that drives the cGAS-STING innate-immune and SASP axis (see §“Chronic DDR signaling drives senescence” below). Chen et al. 2025 (Science) establish a parallel intra-nuclear role: nuclear cGAS binds chromatin at DNA damage sites and suppresses homologous-recombination by limiting the fanci–rad50 interaction required for HR initiation ⁷. This places cGAS as a DDR pathway-choice regulator — a transient brake favouring NHEJ over HR at the moment of damage.

In normal mammals the brake is self-limiting: trim41 (an E3 ubiquitin ligase) rapidly ubiquitinates chromatin-bound cGAS, targeting it for extraction by the p97 segregase, so HR can proceed once the transient block is relieved ⁷. Naked mole rat (NMR) cGAS harbours a four-amino-acid divergence that renders it resistant to TRIM41-mediated eviction; prolonged chromatin retention in NMR cells correlates with enhanced HR efficiency — a finding consistent with the NMR’s unusually robust genomic-stability phenotype ⁷. Liu et al. 2018 (Nature) identified the initial nuclear chromatin-binding activity of cGAS ⁸; Chen 2025 resolves the functional consequence for repair pathway choice and the species-specific regulatory mechanism.

This integrates with the page’s existing Rodier two-arm SASP framing: cytosolic cGAS-STING was already the canonical DDR → IFN/SASP arm; the Chen 2025 finding establishes a mechanistically distinct, intra-nuclear DDR-regulatory arm operating upstream of the cytoplasmic immune signal.

no-fulltext-access — Chen 2025 cited from abstract only; quantitative details (fold-changes, cell line, HR assay) require full-text access for verification. See chen-2025-nmr-cgas-hr-repair.

Checkpoint effector kinases

CHK2 (CHEK2): the ATM effector

CHK2 is phosphorylated by ATM at Thr68 → CHK2 dimerises and autophosphorylates → active CHK2 dissociates and phosphorylates:

p53 at Ser20 → blocks MDM2 binding → p53 stabilisation (→ see p53-pathway for downstream programs)
CDC25A → proteasomal degradation → CDK2 inhibition → G1/S checkpoint
CDC25C → 14-3-3 binding → cytoplasmic sequestration → CDK1 inhibition → G2/M checkpoint

CHK2 loss-of-function variants (CHEK2 1100delC) are moderate-penetrance cancer risk alleles in humans (~2–3× breast cancer risk), confirming functional importance in tumour suppression.

CHK1 (CHEK1): the ATR effector

CHK1 is the primary ATR substrate (Ser317/345) and the dominant checkpoint kinase in S-phase and G2:

CDC25A degradation → intra-S checkpoint (slows origin firing)
CDC25C sequestration → G2/M checkpoint (prevents CDK1 activation)
RAD51 activation (via RPA phosphorylation) — promotes fork restart
WEE1 activation — CDK1 Tyr15 phosphorylation → additional CDK1 inhibition

CHK1 inhibitors (prexasertib, LY2603618) are in oncology trials, exploiting replication stress in cancer cells.

Repair pathway choice

The DDR signals but does not itself repair DNA — it selects among specialized repair pathways depending on lesion type and cell-cycle phase.

Double-strand break repair

HR — homologous recombination (high-fidelity, S/G2)

HR uses the sister chromatid as a template for error-free DSB repair ⁹. Requires:

DSB resection: MRE11 + CtIP initial clipping → Exo1 / DNA2-BLM long-range resection → ssDNA 3′ overhang
RPA → RAD51 exchange: BRCA2 (mediated by PALB2) displaces RPA and loads RAD51 onto ssDNA → RAD51 nucleoprotein filament
Strand invasion: RAD51 filament invades intact sister chromatid at homologous sequence → D-loop
DNA synthesis and resolution: templated synthesis across the break; Holliday junction resolution (dissolution via BLM-TOPO3α-RMI1/2, or resolution via MUS81-EME1)

BRCA1 and BRCA2 mutations abolish HR → cells rely on error-prone NHEJ → accumulation of mutations → cancer predisposition. This is why BRCA1/2 mutation carriers have ~70% lifetime breast cancer risk.

Extrapolation	Status
Pathway conserved in humans?	yes — core RAD51 mechanism identical in mammals
Phenotype conserved in humans?	yes — BRCA1/2 cancer syndromes confirm in vivo necessity

NHEJ — non-homologous end-joining (error-prone, all phases)

NHEJ is the dominant DSB repair pathway in mammalian somatic cells ¹⁰:

Ku70–Ku80 binds directly to DNA ends → recruits DNA-PK
DNA-PK autophosphorylation → end-processing by Artemis (hairpin opening, end trimming)
XRCC4–DNA ligase IV–XLF complex → ligation

NHEJ does not require a template; it directly joins DSB ends, often with small insertions/deletions (indels) at the junction. It is the dominant pathway in G1 and quiescent cells. End-processing by Artemis can cause deletions; fill-in synthesis causes insertions — both mutagenic outcomes accumulate with age.

MMEJ / TMEJ — microhomology-mediated end joining (backup, mutagenic)

When classical NHEJ fails or Ku is absent, cells use MMEJ (also called TMEJ, theta-mediated EJ, requiring Polθ). MMEJ uses microhomologies (2–25 bp) flanking the DSB, causing predictable deletions. It is strongly mutagenic and its activity increases when NHEJ or HR components are lost — relevant to aging cells that accumulate HR/NHEJ defects. needs-replication — MMEJ contribution to age-related mutation accumulation not quantified in humans.

Non-DSB repair pathways

Pathway	Lesion type	Key proteins	Cell-cycle dependence
BER (base excision repair)	Oxidised, alkylated bases; SSBs; abasic sites	OGG1, NEIL1/2, APE1, Pol β, XRCC1, PARP1	All phases
NER (nucleotide excision repair)	Bulky adducts, CPDs, 6-4 PPs (UV)	XPC, XPA, TFIIH, XPG, XPF-ERCC1, RPA	All phases
MMR (mismatch repair)	Replication errors, base mismatches	MSH2/6 (MutSα), MLH1/PMS2 (MutLα), EXO1	S/G2
ICL repair (Fanconi anemia)	Interstrand crosslinks (chemotherapy, aldehydes)	FANCD2–FANCI, FANCC, BRCA2, SLX4	S phase

BER declines with age in multiple mammalian tissues, contributing to the accumulation of oxidative lesions (8-oxo-dG). NER deficiency causes xeroderma pigmentosum (XP); global NER deficiency combined with TC-NER deficiency causes Cockayne syndrome (premature aging phenotype). needs-human-replication — whether BER decline with age is a driver (not just a correlate) of tissue aging requires genetic evidence.

DDR outcomes

The DDR produces one of four cellular outputs depending on damage severity, lesion persistence, and cellular context:

DNA damage
    ↓
[Sensor: MRN / RPA / PARP1]
    ↓
[Transducer: ATM / ATR / DNA-PK]
    ↓
[Mediators: γH2AX / MDC1 / 53BP1 / BRCA1]
    ↓                              ↓
[CHK1/CHK2] → p53 stabilisation   [Repair: HR / NHEJ / BER / NER / MMR]
    ↓
[Outcome choice]
    ├── Transient arrest → successful repair → cell-cycle re-entry
    ├── Sustained arrest → [[p53-pathway]] → [[cellular-senescence|senescence]] (chronic DDR)
    └── Severe/persistent damage → [[p53-pathway]] → [[apoptosis-pathway|apoptosis]]

The specific downstream programs (p21/CDKN1A induction, senescence SASP, pro-apoptotic BCL-2 family transcription) are driven by p53-pathway and are described there. This page focuses on the upstream sensing, transduction, and repair machinery.

Role in aging

The DDR is directly implicated in aging through three interconnected mechanisms:

1. Progressive accumulation of unrepaired lesions

Repair capacity declines with age in multiple systems ⁶:

BER activity falls in aged brain, liver, and lymphocytes (8-oxo-dG accumulates)
NER becomes less efficient; UV-induced CPD removal slows in skin
HR efficiency declines as RAD51 and BRCA1 expression fall in aged tissues needs-replication
DSBs accumulate in aged tissues (γH2AX foci per cell increase with age)

The net result is a rising load of persistent lesions, particularly at difficult loci (heterochromatin, telomeres).

2. Chronic DDR signaling drives senescence (the Rodier model)

Persistent, unresolved DDR signaling — marked by persistent DNA damage foci (PDDF: γH2AX foci that fail to resolve) — drives two separable outputs that together define the senescent state ¹¹:

Growth arrest arm: sustained ATM → CHK2 → p21 signaling locks cells into permanent cell-cycle arrest (this arm also involves p53 and pRb).
SASP arm: ATM, NBS1, and CHK2 are required to initiate and maintain SASP (IL-6, IL-8, and other inflammatory cytokines); p53 and pRb are not required for SASP — the cytokine response can occur in cells that lack functional p53.

These two arms are mechanistically separable: p16INK4a-overexpressing cells undergo arrest without DNA damage and do not develop a SASP, whereas cells with PDDF develop both arrest and SASP. This is distinct from the transient arrest that follows a cleanly repaired break:

Persistent telomeric DDR foci (called TAFs — telomere-associated DDR foci) are a major source of this chronic signaling in aged cells, arising because telomere repeats cannot be repaired by conventional HR ¹¹
Persistent DNA damage foci (PDDF) correlate with SASP induction; cells with low-dose radiation (0.5 Gy, which generates transient DDR that resolves within ~10 h) do not develop SASP, whereas high-dose (10 Gy) generates PDDF and robust SASP — demonstrating that ongoing DDR signaling, not the initial damage event, is the trigger ¹¹
ATM depletion (80–90% knockdown) prevented the X-ray–induced IL-6 increase and abolished pre-existing SASP in already-senescent cells; NBS1 or CHK2 depletion similarly abolished the cytokine response — placing ATM → NBS1 → CHK2 as the required signalling axis ¹¹
The SASP is proposed to amplify damage signals to neighbouring cells; paracrine cytokine effects on invasion and cancer cell behaviour are demonstrated, but a direct feed-forward ROS loop amplifying DDR in neighbours is not established in Rodier 2009 needs-replication

3. Progeroid syndromes: DDR defects accelerate aging

Every major progeroid syndrome is caused by a defect in a DDR component:

Syndrome	Mutated gene	DDR pathway affected	Aging features
Ataxia-telangiectasia	ATM	DSB transduction	Cerebellar degeneration, immunodeficiency, cancer
Werner syndrome	WRN (RecQ helicase)	HR, replication fork restart	Premature aging of skin, hair, vasculature; cancer
Bloom syndrome	BLM (RecQ helicase)	HR (junction resolution)	Growth retardation, immunodeficiency, cancer
Cockayne syndrome	CSB, CSA	TC-NER	Neurodegeneration, cachectic dwarfism, UV sensitivity
Xeroderma pigmentosum	XPA–XPG	Global NER	UV-driven skin aging and cancer; neurodegeneration (XPA)
Nijmegen breakage syndrome	NBN (NBS1)	DSB sensing (MRN)	Microcephaly, immunodeficiency, cancer
Fanconi anemia	FANC genes	ICL repair	Bone marrow failure, cancer

The fact that DDR deficiency phenocopies aging — at the tissue, cellular, and molecular levels — is among the strongest evidence that genomic instability is not merely a correlate but a causal driver of aging ⁶.

Cross-links to aging pathways

Partner	Relationship
p53-pathway	The canonical DDR → p53 stabilization axis. DDR provides the upstream signal; p53 executes the downstream programs (arrest, senescence, apoptosis). The two pages are intentionally separate — see naming note above.
mdm2	ATM and DNA-PK phosphorylate MDM2 at Ser395 (ATM) → inhibiting MDM2’s ability to export p53; this is a parallel mechanism to p53 Ser15 phosphorylation in achieving p53 stabilization.
atm	The primary DSB transducer kinase; described here at pathway level; molecular details on atm protein page (to be drafted).
cellular-senescence	DDR is the proximal trigger for both OIS and telomere-driven senescence; persistent DDR foci are the senescence-inducing signal in aged cells.
genomic-instability	DDR is the cellular surveillance system for this hallmark; its decline with age is mechanistically upstream of genomic instability accumulation.
mtor	mTOR activity promotes cell growth and protein synthesis, increasing ROS and replication stress; mTOR inhibition (rapamycin) reduces DDR activation in some contexts. Indirect relationship; see mtor for details.

Pharmacology (DDR-targeting agents in aging context)

Agent class	Examples	DDR target	Aging relevance
PARP inhibitors (PARPi)	Olaparib, niraparib, rucaparib	PARP1	Clinical (oncology, synthetic lethality in BRCA-mutant tumours); no aging application yet
ATM inhibitors	AZD0156, AZD1390	ATM kinase	Oncology radiosensitisation; could worsen aging if used chronically
ATR inhibitors	Ceralasertib (AZD6738), elimusertib	ATR kinase	Oncology; chronic use would impair replication-stress response
CHK1 inhibitors	Prexasertib (LY2606368)	CHK1	Oncology; ablates S-phase checkpoint
NAD+ precursors	NMN, NR	Indirect: replenish PARP1 substrate	Hypothesised to restore PARP activity and DDR fidelity in aged tissues needs-human-replication
Senolytics	Dasatinib + quercetin, navitoclax	Downstream: clear DDR-senescent cells	Active human trials; address outcome of DDR, not the DDR machinery

The NAD+/PARP connection is particularly relevant: PARP1 consumes NAD+ during SSB repair; excessive PARP activity depletes NAD+ (a metabolic cofactor for sirtuins and mitochondria); NAD+ repletion via NMN/NR may restore PARP’s protective role without the PARP-depletion cost. Mechanistic evidence is strong in model organisms; human DDR restoration data lacking. needs-human-replication

Limitations and gaps

needs-human-replication — Whether decline in BER and NER with age is causal for tissue aging or merely a correlate; genetic DDR-rescue experiments in humans are not feasible.
needs-replication — Quantitative contribution of MMEJ/Polθ to age-related mutagenesis in human tissues is not established.
no-mechanism — The quantitative rules governing repair pathway choice (HR vs NHEJ ratio as a function of cell cycle, damage dose, chromatin context) are partially known but not fully predictive.
contradictory-evidence — Whether chronic low-level ATM/ATR activation (as in aged tissues) is beneficial (triggering repair/clearance) or harmful (driving senescence and inflammation) is context-dependent and not resolved at the tissue level.
needs-human-replication — NAD+/PARP axis as a therapeutic target for restoring DDR fidelity in aging humans: only indirect evidence from model organisms.
DDR pathway pages for individual repair sub-pathways (BER, NER, HR, NHEJ) do not yet exist as atomic pages; this page covers them briefly. stub candidates for future seeding.

Footnotes

doi:10.1038/nature08467 · Jackson SP & Bartek J · review · Nature 2009 · n=N/A · model: human/mammalian · 5862 citations · comprehensive DDR overview covering sensors, transducers, effectors, and disease ↩ ↩²
doi:10.1038/nrm3546 · Shiloh Y & Ziv Y · review · Nature Reviews Molecular Cell Biology 2013 · n=N/A · 1582 citations · comprehensive ATM kinase review including substrate network and A-T phenotype ↩ ↩²
doi:10.1126/science.1083430 · Zou L & Elledge SJ · in-vitro · Science 2003 · n=N/A · 2628 citations · demonstrates RPA-ssDNA recruits ATRIP–ATR; defines the ATR activation mechanism ↩
doi:10.1016/j.molcel.2010.09.019 · Ciccia A & Elledge SJ · review · Molecular Cell 2010 · n=N/A · model: human/mammalian · 4224 citations · detailed mechanistic coverage of DDR modules and repair pathways ↩ ↩² ↩³ ↩⁴
doi:10.1074/jbc.273.10.5858 · Rogakou EP et al. · in-vitro · Journal of Biological Chemistry 1998 · n=N/A · 5316 citations · discovery of γH2AX (H2AX Ser139 phosphorylation) as a DSB mark ↩
doi:10.1056/nejmra0804615 · Hoeijmakers JHJ · review · New England Journal of Medicine 2009 · n=N/A · model: human (progeroid syndromes) · 2146 citations · covers DDR in aging, cancer, and progeroid syndromes — no-fulltext-access (green OA but PDF download failed; claims attributed here are corroborated by Jackson & Bartek 2009 which covers overlapping material) ↩ ↩² ↩³
chen-2025-nmr-cgas-hr-repair · Science 2025 · doi:10.1126/science.adp5056 · PMID 41066557 · #gap/no-fulltext-access · nuclear cGAS suppresses HR via FANCI–RAD50 interaction; TRIM41-mediated ubiquitination + VCP/p97 extraction relieves the brake in WT mammals; NMR cGAS resists eviction → enhanced HR ↩ ↩² ↩³
liu-2018-nuclear-cgas-hr-suppression · n=NR · in-vitro+in-vivo · doi:10.1038/s41586-018-0629-6 · PMID:30356214 · Liu H et al. · Nature 2018 · model: human cell lines + mouse xenograft · “Nuclear cGAS suppresses DNA repair and promotes tumorigenesis” · DOI verified via Crossref; identified nuclear cGAS chromatin-binding activity AND HR-suppressive function; establishes intra-nuclear localisation as distinct from cytosolic immune-sensing role — closed-access; no-fulltext-access for independent quantitative verification ↩
doi:10.1146/annurev.biochem.77.061306.125255 · San Filippo J et al. · review · Annual Review of Biochemistry 2008 · n=N/A · 1646 citations · comprehensive mechanistic review of eukaryotic HR ↩
doi:10.1146/annurev.biochem.052308.093131 · Lieber MR · review · Annual Review of Biochemistry 2010 · n=N/A · 2781 citations · comprehensive mechanistic review of NHEJ in mammals ↩
doi:10.1038/ncb1909 · Rodier F et al. · in-vitro / in-vivo · Nature Cell Biology 2009 · model: human fibroblasts + mouse · 2096 citations · demonstrates persistent DDR foci trigger SASP independently of cell-cycle arrest; foundational for DDR → senescence mechanism (downloaded PDF available) ↩ ↩² ↩³ ↩⁴

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