⚠️ Auto-extracted by Claude on 2026-05-12 — synthesized from canonical UniProt/NCBI metadata and widely-cited primary literature; FANCI-RAD50 / cGAS axis cited from Chen 2025 abstract only due to closed-access PDF (#gap/no-fulltext-access).

RAD50

RAD50 is a 1,312-amino-acid ABC-type ATPase of the SMC (Structural Maintenance of Chromosomes) superfamily. It forms one of three constitutive subunits of the MRN complex (mrn-complex: MRE11–RAD50–NBS1), the primary sensor of DNA double-strand breaks (DSBs) in eukaryotic cells. RAD50’s defining structural feature — a long antiparallel coiled-coil arm capped by a zinc-hook — enables it to physically bridge the two ends of a broken chromosome, holding them in proximity for repair. It is required for both the initiation of homologous-recombination and for early DSB sensing upstream of non-homologous-end-joining. In aging contexts, RAD50 sits at the intersection of three converging biology streams: (1) age-dependent decline of DSB repair efficiency, (2) progeroid-spectrum RAD50-deficiency syndrome (NBSLD), and (3) a newly described pathway in which nuclear cGAS chromatin retention potentiates RAD50 recruitment to damage sites via enhanced FANCI–RAD50 interaction ¹.

Note on HGNC ID: UniProt Q92878 lists HGNC:9816 for RAD50. The mrn-complex page currently records HGNC:9817 — this appears to be a transcription error on that page; HGNC:9816 is the correct identifier per UniProt.

Identity

UniProt: Q92878 (RAD50_HUMAN) — Swiss-Prot (manually curated entry)
NCBI Gene ID: 10111
HGNC: 9816
Ensembl: ENSG00000113522
Length: 1,312 amino acids (canonical isoform)
Mouse ortholog: Rad50 (one-to-one ortholog; highly conserved; null embryonic-lethal in both species)
GenAge: No entry (confirmed null per HAGR GenAge database; see mrn-complex verification notes, 2026-05-07)

Architecture and key domains

RAD50 adopts the canonical SMC-family rod architecture ²:

N-terminal Walker A motif (P-loop) — ATP binding; ~~positioned at the very N-terminus~~, contributes one half of the bipartite ATPase head
C-terminal Walker B motif — ATP hydrolysis; contributes the other half of the ATPase head when the molecule folds in trans back on itself
Central coiled-coil domains — two long antiparallel coiled-coil segments (each ~150–600 Å in length depending on species and structural context) extend away from the globular ATPase head and constitute the “arm” of the rod
Zinc-hook (Cys-X-X-Cys, residues ~635–734) — at the apex of the coiled-coil arm; a conserved CXXC motif coordinates one Zn²⁺ ion with the equivalent motif from a second RAD50 molecule, creating an inter-molecular clamp that can bridge two separate MRN complexes across a DSB ²
ATM-phosphorylation site: Ser-635 is phosphorylated by ATM in trans after DSB-mediated ATM activation, creating a feedback mark on the sensor itself ³

The ATPase head, formed by apposition of the Walker A and Walker B motifs from the same polypeptide (intra-molecular folding), directly contacts the MRE11 dimer, coupling ATP-dependent conformational changes to MRE11 nuclease activity.

Function

DSB end-binding and end-tethering

RAD50, as part of MRN, binds free DNA ends rapidly after DSB formation. The ATPase head contributes to sequence-independent DNA-end binding; RAD50 can bind blunt ends, 5’ or 3’ overhangs, and hairpin structures ⁴. Most distinctively, RAD50 bridges the two broken ends: zinc-hook-mediated RAD50–RAD50 dimerization between two MRN complexes, each bound to one DSB end, can hold the ends in proximity across a gap of up to ~1,200 Å ². This tethering function is essential for rejoining the break and explains why RAD50 zinc-hook mutations confer severe radiation sensitivity in yeast (C1G mutant: ~5-fold increased sensitivity at 300 Gy; C2G mutant: ~95-fold increased sensitivity) ².

ATP-dependent modulation of MRE11 nuclease activity

RAD50’s ATPase cycle regulates MRE11 exonuclease activity: when Mre11 is in complex with Rad50, the 3’→5’ exonuclease activity is increased 3- to 4-fold relative to Mre11 alone ⁴. ATP hydrolysis drives conformational cycling between an “open” (DNA-accepting) and “closed” (DNA-engaging) state at the ATPase head, toggling MRE11 between nuclease-active and -inactive configurations. In the full M/R/N complex with NBS1, these ATP-dependent nuclease and unwinding activities are further potentiated, enabling more efficient hairpin cleavage and generation of single-stranded DNA (ssDNA) tails ⁵.

ATM activation and signaling

RAD50 is an obligate upstream component of ATM activation. MRN (including RAD50) physically tethers inactive ATM dimers to DSB ends via NBS1’s C-terminal FXF/Y–ATM-FATC interaction. ATP-dependent RAD50 conformational changes and MRN-stimulated DNA unwinding contribute to the allosteric transition that dissociates ATM dimers and promotes Ser1981 autophosphorylation — the canonical ATM activation step ⁶. This is detailed on the atm and mrn-complex pages.

End resection licensing for HR

In S/G2-phase cells where homology-directed repair is preferred, MRN initiates end resection. The combined MRE11 nuclease activity (stimulated by RAD50 and further amplified by NBS1) generates an initial incision ~15–20 nt internal to the break end, providing an entry point for long-range resection by EXO1 and DNA2/BLM ⁵. RAD50’s structural role (holding the broken ends together) is required for productive MRE11 endonuclease access to protein-adduct-blocked or chemically-modified ends. Downstream, the ssDNA tails are coated by rpa → RAD51 loading by brca2 → HR template search.

HR vs NHEJ pathway choice

RAD50-containing MRN competes with the ku70-ku80 heterodimer at DSB ends. When Ku loads first (favored in G1 phase), DNA ends are shielded from resection and committed to NHEJ. When MRN loads and initiates resection (favored in S/G2), the single-stranded tail substrate is unsuitable for Ku, committing the break to HR. Cell-cycle-phase regulation of CDK activity influences this competition by phosphorylating key resection factors (e.g., CtIP/RBBP8, which cooperates with MRN at the initial incision step).

In aging

Declining DSB repair efficiency

HR efficiency declines with age in human primary cells. In a study of 50 eyelid fibroblast lines from donors aged 16–75 years, both NHEJ efficiency/fidelity and HR efficiency decreased with donor age, with RAD51 showing stable protein levels but slow recruitment kinetics to damage sites in aged cells ⁷. This was the work of the Mao group (same laboratory that published Chen 2025), suggesting a long-standing research interest in age-associated DDR decline. The specific MRN/RAD50 contribution to this age-associated HR inefficiency was not directly measured in that study — RAD50 protein levels and complex stability in aged human primary cells have not been separately quantified. needs-replication

The age-related DSB burden (documented by increased γH2AX foci in aged tissues) combined with declining HR efficiency implicates MRN sensing and RAD50-mediated end-tethering as rate-limiting steps in aged tissue repair. Whether RAD50 itself, or downstream HR factors (RAD51, BRCA1/2), are the primary rate-limiting node has not been established. no-mechanism

Progeroid overlap: RAD50 deficiency (NBSLD)

Loss-of-function mutations in RAD50 cause Nijmegen breakage syndrome-like disorder (NBSLD), first described by Waltes et al. 2009 ⁸. The index patient presented with:

Microcephaly
Intellectual disability
Bird-like facies, short stature
Chromosomal instability
Radiation hypersensitivity
Impaired MRN foci formation at DSBs
Defective ATM activation and downstream signaling
Radioresistant DNA synthesis and G2-phase accumulation

The cellular phenotype was rescued by wild-type RAD50 transfection, definitively attributing the syndrome to RAD50 loss ⁸. Unlike typical NBS (NBN/NBS1 hypomorphism), the index patient did not develop lymphoid malignancy and had normal immunoglobulin levels through age 23 — indicating distinct clinical consequences for RAD50 vs NBS1 deficiency, though both impair ATM activation. A subsequent cohort confirmed this as a distinctive phenotype ⁹; additional patients with compound heterozygous RAD50 variants have since presented with bone marrow failure and B-cell immunodeficiency ¹⁰.

The NBSLD phenotype — microcephaly, growth failure, chromosomal instability — overlaps the progeroid-spectrum DDR-deficiency syndromes (NBS, ATLD, A-T) and reflects the consequences of impaired DSB sensing in developing tissues with high replicative demand. These syndromes collectively demonstrate that RAD50 loss-of-function phenocopies accelerated genomic instability and tissue deterioration relevant to aging biology.

Dimension	Status
RAD50 function conserved in aging-relevant contexts?	yes — DSB repair, ATM activation, and HR are highly conserved; ortholog phenotypes identical
Progeroid phenotype from RAD50 loss in humans?	yes — NBSLD established ⁸⁹
Direct measurement of RAD50 activity decline with age?	no — not done in primary human cells needs-replication

EPAS1-driven RAD50 transcription and telomere protection

In bat fibroblasts and human pulmonary endothelial cells, the transcription factor EPAS1 (HIF-2α) upregulates RAD50 transcription alongside the shelterin components TRF1 and TRF2, protecting cells from telomeric-damage-induced senescence during extended culture ¹¹. This places RAD50 downstream of the hypoxia-inducible factor pathway as part of a telomere-protection gene program. Whether EPAS1-driven RAD50 upregulation is protective against age-associated telomere erosion in human somatic tissues has not been tested. needs-human-replication

The FANCI–RAD50 axis and nuclear cGAS chromatin retention (Chen 2025)

A 2025 Science paper from the Mao lab ¹ identified a new regulatory layer on RAD50 function via a study of naked mole-rat (NMR) cGAS. NMR-cGAS carries four amino acid substitutions relative to human/mouse cGAS that prevent its eviction from chromatin by the ubiquitination machinery (TRIM41 and the P97 segregase). This prolonged chromatin retention — beyond the duration of the acute DSB response — enhances the interaction between repair factors FANCI and RAD50, facilitating RAD50 recruitment to damage sites and potentiating HR repair (abstract verbatim: “Prolonged chromatin binding of cGAS enhanced the interaction between repair factors FANCI and RAD50 to facilitate RAD50 recruitment to damage sites, thereby potentiating homologous recombination repair”).

Mechanistic implications:

FANCI as a RAD50 co-factor: FANCI is a Fanconi anemia pathway protein classically associated with interstrand crosslink (ICL) repair; its role in modulating RAD50 recruitment to DSBs (rather than ICLs alone) represents a newly described function. Whether this FANCI–RAD50 interaction was previously described in the ICL-repair context or is entirely novel to the Chen 2025 paper is unclear from the abstract. needs-replication
cGAS as a DDR potentiator (not just innate immune sensor): This extends the known biology of cgas-sting as a sensor of cytoplasmic DNA into a chromatin-bound DDR-enhancement role. The NMR cGAS four-aa substitutions confer both prolonged chromatin retention and downstream HR potentiation; transferring these substitutions to human cGAS might replicate the effect in human cells (not yet tested). no-mechanism
cGAS-centric aging attenuation: The paper reports that the same NMR cGAS properties that potentiate HR “contribute to cellular and tissue aging suppression, extending lifespan” (DOI lookup summary). This links enhanced RAD50 recruitment — downstream of prolonged cGAS chromatin retention — to organism-level lifespan extension in a mammalian system. needs-replication

Citation limitation: Chen 2025 is closed-access (oa_status: closed; not_oa) and the local PDF is not available. The above is sourced from the abstract and DOI lookup only. Specific mechanistic details (co-IP data, focus quantification, dose-response) are not independently accessible. no-fulltext-access

Pathway membership

dna-damage-response — upstream sensor; RAD50/MRN is the first responder to DSBs
homologous-recombination — initiates end resection that licenses HR; required for productive RAD51 loading
non-homologous-end-joining — MRN participates in early DSB detection upstream of Ku; pathway choice is competitive

Key interactors

mrn-complex — RAD50’s obligate complex; structural and functional description of MRE11–RAD50–NBS1 lives there
atm — master DDR kinase; MRN (requiring RAD50’s end-tethering and NBS1-ATM contact) is required for ATM activation at DSBs ⁶
ku70-ku80 — NHEJ sensor; competes with MRN at DSB ends for pathway commitment
brca2 — downstream of MRN-initiated resection; loads RAD51 onto ssDNA for HR
rpa — coats the 3’ ssDNA overhangs produced by MRN-initiated resection
p53 — phosphorylated at Ser15 by ATM activated downstream of MRN sensing; links DSB signaling to cell-fate decisions
cgas-sting — cGAS chromatin retention potentiates FANCI–RAD50 interaction and HR (Chen 2025) ¹; separately, unrepaired DSB fragments are a cGAS-activating ligand

Druggability

Tier 3 — predicted druggable (research stage only; no aging-context clinical drug exists).

No approved drug targets RAD50 directly. The mrn-complex page (druggability tier 3) notes that small-molecule MRE11 inhibitors (mirin, PFM series) are research tools. RAD50 structural features — the ATP-binding site, the zinc-hook CXXC motif — are in principle druggable. Zinc-hook disruption (via CXXC-competitive agents) would sever end-tethering, and ATPase-cycle inhibitors could lock RAD50 in a non-productive conformation.

Aging-context rationale: As with the MRN complex as a whole, the therapeutic direction for aging biology is the inverse of standard oncology logic. Inhibiting RAD50 would worsen genomic instability — the relevant aging target is maintaining or restoring RAD50 function in aged tissues. Allosteric activators, FANCI–RAD50 interaction promoters, or approaches mimicking NMR-cGAS chromatin retention (Chen 2025) represent speculative but mechanistically grounded strategies. None has entered clinical or late-preclinical development. no-mechanism

Open Targets Platform API was unavailable during seeding (HTTP 500). Tier 3 assignment based on MRN complex page precedent and absence of clinical-stage compounds in DrugBank/ChEMBL. Recommend re-checking via api.platform.opentargets.org on next lint pass.

Knowledge gaps and limitations

#gap/needs-replication — RAD50 protein levels, complex stability, and end-tethering activity have not been directly quantified in aged primary human cells. The HR efficiency decline with age (Li/Mao 2016 ⁷) was not decomposed into MRN vs RAD51 vs BRCA1/2 contributions.
#gap/needs-replication — FANCI–RAD50 interaction as a regulatory node of HR (Chen 2025 ¹): whether this interaction is the primary HR-rate-limiting step in aged human cells, or whether it is a species-specific enhancement operative in NMR, requires follow-up.
#gap/no-fulltext-access — Chen 2025 (doi:10.1126/science.adp5056) is closed-access (not_oa, no local PDF). Mechanistic details beyond the abstract are not available for verification.
#gap/no-mechanism — Precise role of RAD50’s ATP hydrolysis cycle in licensing vs inhibiting MRE11 nuclease activity in aged cells has not been studied.
#gap/no-mechanism — Whether EPAS1-driven RAD50 transcription (Li 2023 ¹¹) contributes to the age-associated decline in HR efficiency has not been tested in aged human tissues.
#gap/needs-human-replication — EPAS1/RAD50 telomere-protection axis studied primarily in bat cells; replicated with human pulmonary endothelial cells in culture only; not tested in aged human tissue.
#gap/needs-canonical-id — Open Targets Platform druggability tier was not retrievable (API error at seeding); tier 3 is inferred from MRN complex page context. Re-verify via Ensembl ID ENSG00000113522 on next lint pass.
#gap/unsourced — MRN complex page records HGNC:9817 for RAD50; UniProt Q92878 confirms HGNC:9816. The discrepancy is noted but correction of the MRN complex page is deferred to the next propagation pass.

Footnotes

chen-2025-nmr-cgas-hr-repair · Science 2025 · doi:10.1126/science.adp5056 · PMID: 41066557 · in-vivo + cell biology · model: naked mole-rat cGAS variants in NMR and human cells · no-fulltext-access (closed-access; not_oa; abstract-only citation) · citation count: 17; FWCI: 44.04 (100th percentile impact) ↩ ↩² ↩³ ↩⁴
doi:10.1038/nature00922 · Hopfner KP et al. · Nature 2002 · in-vitro (crystal structure + yeast genetics) · model: Pyrococcus RAD50 zinc-hook crystal structure (2.2 Å) + human/Pyrococcus EM + yeast C1G/C2G mutants · locally available (see mrn-complex footnotes) ↩ ↩² ↩³ ↩⁴
doi:10.3390/biom5042877 · Lavin MF et al. · Biomolecules 2015 · review · model: human DDR (ATM-dependent phosphorylation of MRN subunits) · locally available (see mrn-complex footnotes) ↩
doi:10.1016/s1097-2765(00)80097-0 · Paull TT, Gellert M · Molecular Cell 1998 · in-vitro (biochemical reconstitution) · model: purified human MRE11 + RAD50 (baculovirus-expressed) · locally available (see mrn-complex footnotes) ↩ ↩²
doi:10.1101/gad.13.10.1276 · Paull TT, Gellert M · Genes & Development 1999 · in-vitro (biochemical reconstitution) · model: purified human MRE11/RAD50/NBS1 triple complex · locally available (see mrn-complex footnotes) ↩ ↩²
doi:10.1126/science.1108297 · Lee JH, Paull TT · Science 2005 · in-vitro (reconstituted human proteins) · model: recombinant human MRN + ATM · PMID: 15790808 · no-fulltext-access (not_oa, no PMC deposit; cross-checked via atm and mrn-complex) ↩ ↩²
doi:10.1038/cdd.2016.65 · Li Z, Zhang W, Chen Y, Guo W, Zhang J, Tang H, Xu Z, Zhang H, Tao Y, Wang F, Jiang Y, Sun FL, Mao Z · Cell Death Differ 2016 · observational · n=50 human fibroblast lines (donors aged 16–75 yr) · model: human primary fibroblasts, age-stratified · PMID: 27391797 · citation percentile: 100% · not locally downloaded (status: pending) ↩ ↩²
doi:10.1016/j.ajhg.2009.04.010 · Waltes R, Kalb R, Gatei M, Kijas AW, Stumm M, Sobeck A, Wieland B, Varon R, Lerenthal Y, Lavin MF, Schindler D, Dörk T · Am J Hum Genet 2009 · n=1 (proband; compound heterozygous RAD50 mutations) · case-report + cell biology · model: patient fibroblasts + wild-type RAD50 rescue · PMID: 19409520 · citation percentile: 100% (256 citations) · not locally downloaded (status: pending, bronze OA) ↩ ↩² ↩³
doi:10.1002/ajmg.a.61570 · Ragamin A et al. · Am J Med Genet A 2020 · n=1 + literature review · case-report · model: RAD50-deficient patient cells · PMID: 32212377 · not locally downloaded (status: pending, hybrid OA) ↩ ↩²
doi:10.1007/s10875-023-01591-8 · Takagi M et al. · J Clin Immunol 2023 · n=1 · case-report · model: compound heterozygous RAD50 patient (p.Arg83His + p.Glu485Ter) · PMID: 37794136 ↩
doi:10.24272/j.issn.2095-8137.2022.531 · Li KQ et al. · Zoological Research 2023 · in-vitro (bat fibroblasts + human pulmonary endothelial cells) · model: EPAS1 knockdown/overexpression; bleomycin-induced telomere damage · PMID: 37070589 · diamond OA (status: pending download) ↩ ↩²

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