Affinage

RAD51C

DNA repair protein RAD51 homolog 3 · UniProt O43502

Length
376 aa
Mass
42.2 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAD51C is a RAD51 paralog that serves as the indispensable hub of two distinct complexes—BCDX2 (RAD51B–RAD51C–RAD51D–XRCC2) and CX3 (RAD51C–XRCC3)—through which it orchestrates homologous recombination, replication fork protection, and Holliday junction resolution. Structurally, RAD51C–RAD51D–XRCC2 within BCDX2 mimics three RAD51 protomers in a nucleoprotein filament, and the coupled ATPase activities of RAD51B and RAD51C drive nucleation and extension of RAD51 filaments on ssDNA, while the CX3 complex provides a separable 5′ RAD51 filament capping function and catalyzes branch migration and resolution of Holliday junctions (PMID:37344587, PMID:37488098, PMID:14716019). Beyond its core recombination activities, RAD51C facilitates RAD51 nuclear import, activates CHK2-dependent DNA damage checkpoint signaling, stimulates ALKBH3-mediated alkylation repair, and maintains mitochondrial DNA integrity at nucleoids (PMID:19783859, PMID:19451272, PMID:31642493, PMID:29158291). RAD51C functions as a tumor suppressor whose loss confers PARP inhibitor and cisplatin sensitivity; biallelic mutations cause a Fanconi anemia–like cellular phenotype, and saturation genome editing has classified thousands of variants as functionally disruptive with clinical relevance to breast and ovarian cancer (PMID:19155299, PMID:23512992, PMID:22167183, PMID:39299233).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 Medium

    Identification of RAD51C as a new RAD51 family member and demonstration of its heterodimerization with XRCC3 and RAD51B established the concept that RAD51 paralogs form specific heteromeric pairs rather than homomeric assemblies.

    Evidence Yeast two-hybrid screen with cDNA cloning

    PMID:9469824

    Open questions at the time
    • Yeast two-hybrid only, no biochemical validation of direct binding
    • Stoichiometry and higher-order complexes unknown
    • Functional significance of paralog interactions uncharacterized
  2. 2001 High

    Biochemical reconstitution of RAD51C-containing complexes revealed that RAD51C–XRCC3 catalyzes homologous pairing while RAD51B–RAD51C acts as a recombination mediator that relieves RPA competition with RAD51, establishing the first enzymatic activities for RAD51 paralogs.

    Evidence Purified recombinant complexes from baculovirus expression; homologous pairing assay, strand exchange assay, ATPase assay, electron microscopy

    PMID:11331762 PMID:11459987 PMID:11751636

    Open questions at the time
    • Activities measured with isolated subcomplexes, not full BCDX2
    • Relationship between in vitro pairing activity and in vivo HR function untested
    • No structural information on complex architecture
  3. 2002 High

    Co-immunoprecipitation from multiple human and hamster cell lines defined RAD51C as the obligate shared subunit of two distinct complexes—BCDX2 and CX3—and showed that RAD51C loss abolishes both complexes, causing ICL sensitivity, impaired RAD51 focus formation, and a unique sister chromatid cohesion defect.

    Evidence Reciprocal co-IP from HeLa/MCF7/MCF10A cells, RAD51C-null hamster cell lines (irs3, CL-V4B), cytogenetics, SCE assay

    PMID:11744692 PMID:11842112 PMID:11842113 PMID:11912211 PMID:12000837

    Open questions at the time
    • Structural basis for RAD51C's central bridging role unknown
    • Whether the two complexes act sequentially or in parallel during HR unresolved
    • Sister chromatid cohesion mechanism not molecularly defined
  4. 2004 High

    Immunodepletion/complementation experiments demonstrated that RAD51C is essential for Holliday junction branch migration and resolution, while Walker A box mutagenesis showed its ATPase activity is required for HR, defining RAD51C's catalytic contributions to late recombination steps.

    Evidence Cell-free HJ resolvase assay with immunodepletion and reconstitution; site-directed mutagenesis with gene conversion assay in RAD51C-deficient cells

    PMID:12966089 PMID:14716019 PMID:15141025

    Open questions at the time
    • Identity of the resolvase active site (RAD51C vs. associated nuclease) unresolved
    • Relationship between BCDX2 branch-DNA binding and CX3 resolvase activity unclear
    • No atomic structure of any RAD51C complex
  5. 2007 High

    Mouse genetics revealed RAD51C is essential for embryonic viability and meiotic chromosome segregation, with sex-specific meiotic defects and direct tumor suppressor function on a Trp53-null background, extending RAD51C's roles beyond mitotic HR.

    Evidence Rad51c null and hypomorphic mouse alleles; meiotic cytology; Rad51c/Trp53 double-mutant tumor analysis

    PMID:17312021 PMID:19155299

    Open questions at the time
    • Molecular basis of sex-specific meiotic phenotypes unclear
    • Tumor spectrum limited to sebaceous gland tumors in mouse; relevance to human cancer types not established genetically
  6. 2009 High

    RAD51C was placed in the DNA damage signaling pathway downstream of ATM/NBS1/RPA and upstream of both RAD51 assembly and CHK2 checkpoint activation, and shown to facilitate RAD51 nuclear import, revealing dual roles in repair and checkpoint signaling.

    Evidence Epistasis analysis with siRNA knockdowns of ATM/NBS1/RPA; CHK2 phosphorylation assay; subcellular fractionation showing RAD51C-dependent RAD51 nuclear accumulation

    PMID:19451272 PMID:19783859

    Open questions at the time
    • Mechanism by which RAD51C activates CHK2 not molecularly defined
    • Whether RAD51C directly chaperones RAD51 or acts indirectly on nuclear import unresolved
    • Whether checkpoint and repair functions are separable in vivo untested
  7. 2013 High

    Discovery of RAD51C within a PALB2–BRCA2–RAD51C complex and demonstration that RAD51C-deficient cells are sensitive to PARP inhibitors connected RAD51C to the BRCA-mediated repair network and identified a clinically exploitable vulnerability.

    Evidence Co-IP and direct binding assays for PALB2–RAD51C–BRCA2; bidirectional PARP inhibitor sensitivity manipulation (knockdown/rescue) in vitro and xenograft models

    PMID:23512992 PMID:24141787

    Open questions at the time
    • Whether PALB2–BRCA2–RAD51C complex is distinct from or overlapping with BCDX2/CX3 unclear
    • Mechanisms of acquired PARP inhibitor resistance in RAD51C-deficient tumors not defined
  8. 2018 Medium

    Localization of RAD51C/XRCC3 to mitochondrial nucleoids and demonstration that their loss impairs mtDNA synthesis revealed a nucleus-independent DNA maintenance function.

    Evidence ChIP on mitochondrial DNA, mtDNA synthesis assay, Twinkle-dependent localization, siRNA knockdown

    PMID:29158291

    Open questions at the time
    • Single lab finding awaiting independent replication
    • Whether mitochondrial function uses the same CX3 complex or a distinct pool of RAD51C is unknown
    • Contribution to mitochondrial genome stability versus nuclear HR in disease settings unclear
  9. 2019 High

    Identification of a direct RAD51C–ALKBH3 interaction that stimulates demethylation of alkyl adducts on 3′-tailed DNA expanded RAD51C's repertoire to alkylation damage repair.

    Evidence Co-IP, in vitro pull-down, reconstituted ALKBH3 demethylation assay with RAD51C, cell-based alkylation repair

    PMID:31642493

    Open questions at the time
    • Whether this function operates through BCDX2, CX3, or free RAD51C unknown
    • In vivo physiological significance for alkylation-induced mutagenesis or tumorigenesis not established
  10. 2023 High

    Cryo-EM structure of BCDX2 and X-ray crystal structure of CX3 resolved the atomic architectures, showing BCDX2 mimics a RAD51 filament segment that nucleates and extends RAD51 on ssDNA, while CX3 has a polymerization motif enabling 5′ filament capping and separable fork protection/restart functions.

    Evidence Cryo-EM (BCDX2), X-ray crystallography (CX3), single-molecule RAD51 filament assays, CRISPR-edited human cell complementation, ATPase assays

    PMID:37344587 PMID:37488098

    Open questions at the time
    • No structure of BCDX2 or CX3 bound to DNA substrate
    • How CX3 polymerization motif interfaces with RAD51 filament ends in vivo is modeled but not structurally captured
    • Coordination between BCDX2 nucleation and CX3 capping during a single HR event remains hypothetical
  11. 2024 High

    Saturation genome editing functionally classified >3,000 RAD51C variants as disruptive, providing a near-complete variant effect map validated against cancer cohorts and confirming that the Walker A region and paralog interaction interfaces are the most mutationally sensitive domains.

    Evidence Saturation genome editing in HAP1 cells, Gaussian mixture modeling, validation against UK Biobank and ovarian cancer cohort

    PMID:39299233

    Open questions at the time
    • SGE readout is cell fitness, not a direct HR assay; some HR-specific hypomorphic variants may be missed
    • Clinical penetrance of individual variants not determined by SGE alone
    • No saturation mutagenesis data for mitochondrial or checkpoint-specific functions

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BCDX2 and CX3 are coordinately deployed during a single HR event—their temporal handoff, regulation by post-translational modifications, and the structural basis of RAD51C's checkpoint signaling through CHK2—remains unresolved.
  • No structure of either complex engaged with a DNA substrate or RAD51 filament
  • Mechanism of CHK2 activation by RAD51C molecularly undefined
  • Clinical classification of the full missense variant landscape for non-HR functions (checkpoint, mtDNA, alkylation repair) lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140657 ATP-dependent activity 5 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-73894 DNA Repair 9 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-69306 DNA Replication 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
ALKBH3BRCA2PALB2POLGRAD51BRAD51DXRCC2XRCC3
Complex memberships
BCDX2 (RAD51B–RAD51C–RAD51D–XRCC2)CX3 (RAD51C–XRCC3)PALB2–BRCA2–RAD51C

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RAD51C was isolated as a new member of the RAD51 family, and yeast two-hybrid experiments showed that RAD51C protein binds to XRCC3 and RAD51B but not to itself, indicating heterodimeric interactions among RAD51 paralogs. Yeast two-hybrid assay, cDNA cloning Nucleic acids research Medium 9469824
2001 RAD51C and XRCC3 co-purify as a stable complex from baculovirus-infected insect cells and form an endogenous complex in HeLa cells; purified RAD51C–XRCC3 binds single-stranded DNA to form protein–DNA networks visible by electron microscopy. Baculovirus expression, co-purification, co-immunoprecipitation from HeLa cells, electron microscopy Proceedings of the National Academy of Sciences of the United States of America High 11459987
2001 The purified XRCC3·RAD51C complex catalyzes homologous pairing; RAD51C alone also shows homologous pairing activity (reduced), indicating RAD51C is the catalytic subunit, while XRCC3 is required for DNA binding. The complex forms filamentous structures with circular ssDNA. Biochemical reconstitution (purified proteins), homologous pairing assay, electron microscopy Proceedings of the National Academy of Sciences of the United States of America High 11331762
2001 RAD51B and RAD51C form a stable in vivo and in vitro heterocomplex; immunoprecipitation from HeLa, MCF10A, and MCF7 cells shows RAD51C is central to a large complex with RAD51B, RAD51D, XRCC2, and XRCC3, but RAD51 itself is not included in these complexes. Immunoaffinity chromatography, co-immunoprecipitation from human cell lines The Journal of biological chemistry High 11744692
2001 The RAD51B–RAD51C complex has ssDNA binding and ssDNA-stimulated ATPase activities, and functions as a recombination mediator by relieving RPA competition with RAD51 for ssDNA substrate binding, promoting RAD51-catalyzed DNA strand exchange. Biochemical reconstitution, ssDNA-stimulated ATPase assay, DNA strand exchange assay Genes & development High 11751636
2002 Immunoprecipitation in human cells demonstrates RAD51C exists in two distinct in vivo complexes: RAD51B–RAD51C–RAD51D–XRCC2 (BCDX2) and RAD51C–XRCC3 (CX3); XRCC2 and RAD51D co-precipitate with RAD51C but not XRCC3, whereas XRCC3 pulls down with RAD51C but not XRCC2 or RAD51D. RAD51 co-precipitates with XRCC3, suggesting an XRCC3–RAD51C–RAD51 complex. Co-immunoprecipitation with epitope-tagged RAD51 paralogs in human cells Nucleic acids research High 11842113
2002 Rad51C protein is confirmed to interact with XRCC3 in human cells via Ni2+-binding pull-down; Rad51C but not XRCC3 interacts with Rad51B, Rad51D and XRCC2, confirming at least two complexes (Rad51C–XRCC3 and Rad51B–Rad51C–Rad51D–XRCC2); overexpression of XRCC3 moderately elevates endogenous Rad51C, suggesting dimerization stabilizes Rad51C. Ni2+-binding pull-down in stable human cell lines expressing His-tagged paralogs, Western blotting Nucleic acids research High 11842112
2002 RAD51C deficiency in hamster CL-V4B cells causes hypersensitivity to DNA cross-linking agents and alkylating agents, impaired RAD51 focus formation, increased chromosomal aberrations, reduced sister chromatid exchanges, and a unique defect in sister chromatid cohesion not seen with other RAD51 paralog deficiencies. Cell survival assay, immunofluorescence (RAD51 foci), cytogenetics, BrdU incorporation (SCE assay), cell line characterization Nucleic acids research High 12000837
2002 Recombinant Rad51B and Rad51C form a stable heterodimer; both bind ssDNA and dsDNA with preferential binding to 3'-tailed duplexes; Rad51C has ATPase activity and an ATP-independent DNA strand exchange activity resulting from duplex DNA destabilization; mixing Rad51C with Rad51 or Rad51B enhances DNA binding. Baculovirus expression, Ni-NTA pull-down, DNA-binding assay, ATPase assay, strand exchange assay The Journal of biological chemistry High 12427746
2002 In RAD51L2 (RAD51C)-deficient hamster irs3 cells, neither of the two RAD51 paralog complexes (CX3 and BCDX2) is formed, demonstrating that RAD51C is required for the assembly of both complexes; irs3 cells show reduced SCE, increased isochromatid breaks, and decreased damage-induced RAD51 focus formation. Co-immunoprecipitation, clonogenic survival, SCE assay, cytogenetics, RAD51 focus formation The Journal of biological chemistry High 11912211
2003 Site-directed mutagenesis of the RAD51C ATP-binding domain (Walker A box) severely reduces its function in homologous recombination; a C-terminal domain provisionally identified as a nuclear localization signal is required for nuclear import; RAD51C-deficient cells have significantly reduced gene conversion, partially restored by ectopic RAD51C expression. Site-directed mutagenesis, GFP-tagging/live imaging for localization, gene conversion assay in RAD51C-deficient cells The Journal of biological chemistry High 12966089
2003 Residues 63–346 of XRCC3 constitute the RAD51C-binding region; Tyr139 and Phe249 of XRCC3 are essential amino acid residues for RAD51C binding as shown by point mutagenesis and two-hybrid/biochemical analyses; the XRCC3(63–346)–RAD51C complex retains ssDNA and dsDNA binding activity comparable to the full-length complex. Yeast two-hybrid, biochemical co-purification, DNA binding assay, structure-based mutagenesis Nucleic acids research High 12853621
2004 Extracts from RAD51C- or XRCC3-mutant cells have reduced Holliday junction resolvase activity; depletion of RAD51C from fractionated human extracts abolishes branch migration and resolution activity, which is restored by complementation with RAD51 paralog complexes containing RAD51C, establishing RAD51C's role in HJ processing. Cell-free extract HJ resolvase assay, immunodepletion/complementation, fractionation Science (New York, N.Y.) High 14716019
2004 The BCDX2 complex (RAD51B–RAD51C–RAD51D–XRCC2) preferentially binds branched DNA structures (Y-shaped DNA and synthetic Holliday junctions) and catalyzes strand-annealing between long complementary ssDNA molecules. Competitive DNA-binding assay with multiple substrates, strand-annealing assay, purified human BCDX2 complex Nucleic acids research High 15141025
2004 siRNA depletion of RAD51C in human HT1080 cells significantly reduces homologous recombination frequency; depletion of RAD51C in HeLa cells sharply reduces XRCC3 protein levels, indicating XRCC3 stability depends on heterodimerization with RAD51C; RAD51C-depleted cells are hypersensitive to MMC and ionizing radiation specifically in S and G2/M phases. siRNA knockdown, HR assay, Western blot (XRCC3 stability), clonogenic survival, cell cycle analysis The Journal of biological chemistry High 15292210
2004 XRCC3 ATPase activity (Walker A box K113) is essential for XRCC3–RAD51C complex dynamics; K113A mutant XRCC3 forms a stable complex with RAD51C but lacks complementing activity, while K113R mutant fails to form complex and is insoluble; addition of ATP abolishes complex formation by wild-type proteins, suggesting ATP hydrolysis regulates complex dissociation. Site-directed mutagenesis, bacterial co-expression/Ni-affinity purification, complementation assay in Xrcc3-deficient CHO cells The Journal of biological chemistry High 15037616
2004 Residues 14–25 of RAD51C constitute a hot spot for interactions with both XRCC3 and RAD51B; point mutations in this region alter both interactions in two-hybrid assays; a synthetic peptide of residues 14–25 fused to a membrane transduction domain inhibits RAD51 subnuclear assembly and sensitizes CHO cells to cisplatin. Phage display, yeast two-hybrid mutagenesis, peptide transduction, RAD51 focus formation assay, clonogenic survival Cancer research Medium 15126333
2005 RAD51C has a functional nuclear localization signal; endogenous RAD51C and XRCC3 are detectable in human cells; RAD51C plays a role in regulating ubiquitin-mediated proteasomal degradation of RAD51 during recombinational DNA repair. Subcellular fractionation, immunofluorescence, proteasome inhibitor treatment, Western blot Journal of cellular biochemistry Medium 16215984
2005 RAD51D ATPase motif (Walker A, K113) is required for efficient repair of DNA interstrand crosslinks and for interaction with RAD51C; K113R and K113A mutations reduce ICL repair ~96% and ~83% respectively, and reduce RAD51C interaction 8-fold while retaining XRCC2 interaction. Site-directed mutagenesis, complementation in Rad51d-deficient MEFs, yeast two-hybrid Mutagenesis High 16236763
2006 RAD51C–XRCC3 (80-kDa complex) co-elutes with Holliday junction resolvase activity in gel filtration analyses; RAD51C localizes to mouse meiotic chromosomes at pachytene/diplotene, consistent with a role in resolution of recombination intermediates prior to chromosome segregation. Gel filtration, co-immunoprecipitation, HJ resolvase assay, meiotic chromosome immunofluorescence in mouse The Journal of biological chemistry High 17114795
2006 In RAD51C-deficient CL-V4B hamster cells, gene conversion is inefficient and biased toward long-tract (>3.2 kb) over short-tract events, with a bimodal tract length distribution; wild-type RAD51C restores normal short-tract gene conversion, indicating RAD51C controls the choice between short- and long-tract gene conversion pathways. Site-specific chromosomal double-strand break gene conversion assay, tract length analysis, complementation Molecular and cellular biology High 16954385
2007 In RAD51C-deficient CL-V4B hamster cells, mitotic cells have an increased number of centrosomes resulting in aberrant mitotic spindles; re-expression of human RAD51C in these cells restores normal centrosome numbers, indicating RAD51C is required for maintaining correct centrosome number in mitosis. Centrosome counting by immunofluorescence in Rad51C-deficient cells, complementation Cytogenetic and genome research Medium 17268176
2007 In mice, RAD51C deficiency causes early embryonic lethality; male hypomorphic mice show spermatocyte arrest at early meiotic prophase I (implicating RAD51C in early RAD51-mediated recombination); female hypomorphic mice exhibit normal meiosis until metaphase I but show precocious sister chromatid separation, aneuploidy, and broken chromosomes at metaphase II. Rad51c-null MEFs show marked reduction in HJ resolution activity. Mouse genetics (null and hypomorphic alleles), meiotic cytology, HJ resolution assay in MEFs The Journal of cell biology High 17312021
2009 RAD51C accumulates at DNA damage sites concomitantly with RAD51 recombinase and is retained after RAD51 disassembly; RAD51C recruitment depends on ATM, NBS1, and RPA (occurring after DNA end resection but before RAD51 assembly); RAD51C is required for CHK2 activation and cell cycle arrest in response to DNA damage. Immunofluorescence (kinetics of focus formation), siRNA knockdown of pathway components, epistasis analysis, CHK2 phosphorylation assay The Journal of cell biology High 19451272
2009 Rad51C has a functional nuclear localization signal; there is a DNA damage-induced increase in nuclear Rad51C; siRNA depletion of Rad51C in HeLa and Capan-1 cells reduces steady-state nuclear Rad51 levels and diminishes the DNA damage-induced nuclear increase in Rad51, establishing Rad51C as a facilitator of Rad51 nuclear transport. Subcellular fractionation, siRNA knockdown, Western blot of nuclear/cytoplasmic fractions, immunofluorescence The Journal of biological chemistry High 19783859
2009 The ATR–Chk1 pathway mediates centrosome aberrations in RAD51C-deficient human cells; Rad51C dysfunction leads to centrosome aberrations in an ATR/Chk1-dependent (not ATM-dependent) manner and to increased aneuploidy. siRNA knockdown of ATR/ATM/Chk1, immunofluorescence centrosome counting, gamma-H2AX foci, aneuploidy analysis Nucleic acids research Medium 19403737
2009 Loss of Rad51c leads to early embryonic lethality in mice; on a Trp53-null background lethality is delayed; Rad51c mutation in DH-cis mice (allowing LOH of both Rad51c and Trp53) promotes development of tumors of specialized sebaceous glands and suppresses typical Trp53 tumors, providing direct in vivo evidence for a tumor suppressor function of Rad51c. Mouse genetics (null allele, double heterozygous trans and cis crosses), tumor analysis Cancer research High 19155299
2011 RAD51C deficiency leads to ICL sensitivity, chromatid-type errors, and G2/M accumulation (FA-like phenotype); RAD51C is dispensable for ICL unhooking and FANCD2 monoubiquitination but is essential for HR downstream of these steps; RAD51C controls intra-S-phase checkpoint through CHK2 activation; pathological RAD51C mutants identified in FA and cancer patients show distinct impairments in HR versus DNA damage signaling. siRNA knockdown, clonogenic survival, chromosomal aberration analysis, FANCD2 monoubiquitination assay, CHK2 phosphorylation assay, HR assay with cancer-associated mutants The Journal of biological chemistry High 22167183
2013 RAD51C is part of a novel protein complex containing PALB2 and BRCA2; the PALB2 WD40 domain directly and independently binds RAD51C and BRCA2; breast cancer-associated missense mutants of PALB2 WD40 (L939W, L1143P) partially disrupt the PALB2–RAD51C–BRCA2 complex and decrease HR; RAD51C cancer-associated mutants also show decreased complex formation with PALB2. Co-immunoprecipitation in cells, biochemical direct binding assays (in vitro), HR assay, radiation sensitivity assay Oncogene High 24141787
2013 RAD51C-deficient cancer cells are sensitive to PARP inhibitor olaparib due to reduced RAD51 focus formation, G2/M arrest, and apoptosis; RAD51C restoration attenuates olaparib sensitivity; RAD51C silencing in resistant cells restores sensitivity; RAD51C downregulation in some cancers occurs via epigenetic mechanisms. Cell viability assay, flow cytometry (cell cycle/apoptosis), siRNA knockdown/overexpression, RAD51 focus formation, xenograft tumor model Molecular cancer therapeutics High 23512992
2013 Oversized AAV genome transduction (fragmented AAV) is disproportionately reliant on RAD51C-mediated DNA strand-annealing repair and is independent of DNA-PKcs; RAD51C-deficient cells show markedly reduced fAAV transduction, establishing RAD51C's role in this alternative DNA repair pathway. Cell fractionation, Rad51C-deficient cell lines, in vitro and in vivo transduction assays Molecular therapy Medium 23939025
2014 RAD51C-deficient cells show spontaneous PARP1 hyperactivation and enhanced recruitment of NHEJ proteins (KU70, Ligase IV) onto chromatin with increased error-prone NHEJ activity; inhibition of DNA-PKcs or depletion of KU70/Ligase IV rescues PARP inhibitor-induced cell death in RAD51C-deficient cells. Chromatin fractionation, NHEJ activity assay, pharmacological inhibition, siRNA knockdown, clonogenic survival Carcinogenesis Medium 25292178
2016 Estrogen transcriptionally regulates RAD51C expression via an ERα-dependent mechanism in ERα-positive breast cancer cells; estrogen also induces RAD51C assembly into nuclear foci at DSBs, which precedes RAD51 complex recruitment; disruption of ERα signaling (anti-estrogens, ERα siRNA) prevents estrogen-induced RAD51C upregulation. Luciferase reporter assay, siRNA knockdown, immunofluorescence (nuclear foci), pharmacological inhibition Cell cycle (Georgetown, Tex.) Medium 27753535
2018 RAD51C/XRCC3 localizes to mitochondrial nucleoids, including the D-loop region, together with mitochondrial polymerase POLG; this localization depends on Twinkle helicase; RAD51C/XRCC3-deficient cells show reduced mtDNA synthesis, increased mitochondrial DNA lesions, and destabilized POLG on mtDNA, establishing a nucleus-independent role in mtDNA replication and maintenance. Subcellular fractionation, ChIP on mitochondrial DNA, mtDNA synthesis assay, immunofluorescence, siRNA knockdown Molecular and cellular biology Medium 29158291
2019 RAD51C directly interacts with alkylation demethylase ALKBH3; this interaction stimulates ALKBH3-mediated repair of methyl-adducts in 3'-tailed DNA substrates; lack of RAD51C–ALKBH3 interaction impairs ALKBH3 function in vitro and in vivo, revealing a role for RAD51C in alkylation repair upstream of ALKBH3. Co-immunoprecipitation, in vitro pull-down, in vitro ALKBH3 demethylation assay, cell-based alkylation repair assay Nucleic acids research High 31642493
2022 Comprehensive analysis of >50 RAD51C missense variants identifies a cluster of HR-deficient mutations in and around the Walker A box that disrupt ATP hydrolysis, ssDNA binding, and interactions with RAD51B, RAD51D, and XRCC3; structural modeling of BCDX2 and CX3 complexes predicts ATP binding occurs at the interface of RAD51C interactions with other paralogs, analogous to RAD51 filament monomer interactions. HDR assay in reconstituted RAD51C-/- cells, ATPase assay, ssDNA binding assay, co-immunoprecipitation, structural modeling Proceedings of the National Academy of Sciences of the United States of America High 36099300
2023 Cryo-EM structure and AlphaFold2 modeling of BCDX2 reveals that RAD51C–RAD51D–XRCC2 mimics three RAD51 protomers aligned within a nucleoprotein filament, while RAD51B is highly dynamic; BCDX2 stimulates nucleation and extension of RAD51 filaments on ssDNA in reactions requiring the coupled ATPase activities of RAD51B and RAD51C; BCDX2 orchestrates RAD51 assembly for replication fork protection and DSB repair. Cryo-electron microscopy, AlphaFold2 modeling, structural proteomics, biochemical reconstitution, single-molecule analysis, ATPase assay Nature High 37344587
2023 X-ray crystal structure of RAD51C–XRCC3 (CX3) with bound ATP analog defines the complex architecture and reveals separable functions: RAD51C has an unappreciated polymerization motif; cancer patient mutations map to discrete CX3 regions controlling DNA replication fork protection, restart, and reversal through separable DNA-binding and implied 5' RAD51 filament capping functions. X-ray crystallography (CX3 co-crystal), CRISPR/Cas9-edited human cells, single-molecule analysis, single-cell analysis, biophysical measurements, functional complementation Nature communications High 37488098
2024 Saturation genome editing (SGE) of RAD51C functionally classifies 3,094 of 9,188 unique variants as disruptive with >99.9% accuracy; specific missense variants show distinct depletion kinetics consistent with hypomorphic alleles; SGE-depleted variants associate with cancer in UK Biobank and ovarian cancer cohort, functionally validating RAD51C's role in cell fitness via its established HR pathway. Saturation genome editing (SGE), Gaussian mixture modeling, UK Biobank association, ovarian cancer cohort analysis Cell High 39299233

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nature genetics 542 20400964
2017 Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer discovery 334 28588062
2010 Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nature genetics 318 20400963
2015 Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 257 26261251
2004 RAD51C is required for Holliday junction processing in mammalian cells. Science (New York, N.Y.) 245 14716019
2001 Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange. Genes & development 191 11751636
2018 Cost-effectiveness of Population-Based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 Mutation Testing in Unselected General Population Women. Journal of the National Cancer Institute 150 29361001
1998 Isolation and characterization of RAD51C, a new human member of the RAD51 family of related genes. Nucleic acids research 142 9469824
2002 Mammalian Rad51C contributes to DNA cross-link resistance, sister chromatid cohesion and genomic stability. Nucleic acids research 124 12000837
2014 Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Scientific reports 122 24504028
2013 RAD51C-deficient cancer cells are highly sensitive to the PARP inhibitor olaparib. Molecular cancer therapeutics 117 23512992
2002 Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells. Nucleic acids research 110 11842113
2001 Complex formation by the human RAD51C and XRCC3 recombination repair proteins. Proceedings of the National Academy of Sciences of the United States of America 110 11459987
2001 Homologous-pairing activity of the human DNA-repair proteins Xrcc3.Rad51C. Proceedings of the National Academy of Sciences of the United States of America 108 11331762
2011 RAD51C is a susceptibility gene for ovarian cancer. Human molecular genetics 107 21616938
2007 RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. The Journal of cell biology 107 17312021
2013 Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair. Oncogene 104 24141787
2002 Complex formation by the human Rad51B and Rad51C DNA repair proteins and their activities in vitro. The Journal of biological chemistry 100 12427746
2016 Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer. Gastroenterology 98 28024868
2002 Interactions involving the Rad51 paralogs Rad51C and XRCC3 in human cells. Nucleic acids research 97 11842112
2006 Role of RAD51C and XRCC3 in genetic recombination and DNA repair. The Journal of biological chemistry 92 17114795
2012 Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer. Human molecular genetics 88 22843497
2002 Role of mammalian RAD51L2 (RAD51C) in recombination and genetic stability. The Journal of biological chemistry 87 11912211
2010 RAD51C: a novel cancer susceptibility gene is linked to Fanconi anemia and breast cancer. Carcinogenesis 84 20952512
2020 BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases. Journal of ovarian research 83 32359370
2000 17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes. Cancer research 78 11034073
2021 Acquired RAD51C Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma. Cancer research 76 34321239
2009 Loss of Rad51c leads to embryonic lethality and modulation of Trp53-dependent tumorigenesis in mice. Cancer research 76 19155299
2005 Arabidopsis RAD51C gene is important for homologous recombination in meiosis and mitosis. Plant physiology 76 16169964
2011 BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. Breast cancer research and treatment 75 21409391
2009 Cellular redistribution of Rad51 in response to DNA damage: novel role for Rad51C. The Journal of biological chemistry 75 19783859
2001 RAD51C interacts with RAD51B and is central to a larger protein complex in vivo exclusive of RAD51. The Journal of biological chemistry 75 11744692
2004 Preferential binding to branched DNA strands and strand-annealing activity of the human Rad51B, Rad51C, Rad51D and Xrcc2 protein complex. Nucleic acids research 72 15141025
2003 The Drosophila spn-D gene encodes a RAD51C-like protein that is required exclusively during meiosis. Genetics 71 14504227
2012 Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Human molecular genetics 70 22451500
2011 Distinct roles of FANCO/RAD51C protein in DNA damage signaling and repair: implications for Fanconi anemia and breast cancer susceptibility. The Journal of biological chemistry 70 22167183
2009 RAD51C facilitates checkpoint signaling by promoting CHK2 phosphorylation. The Journal of cell biology 69 19451272
2006 Differential regulation of short- and long-tract gene conversion between sister chromatids by Rad51C. Molecular and cellular biology 62 16954385
2022 Enhancing the BOADICEA cancer risk prediction model to incorporate new data on RAD51C, RAD51D, BARD1 updates to tumour pathology and cancer incidence. Journal of medical genetics 57 36162851
2017 Clinical characteristics and outcomes of patients with BRCA1 or RAD51C methylated versus mutated ovarian carcinoma. Gynecologic oncology 55 29233532
2013 Oversized AAV transductifon is mediated via a DNA-PKcs-independent, Rad51C-dependent repair pathway. Molecular therapy : the journal of the American Society of Gene Therapy 54 23939025
2011 RAD51C germline mutations in breast and ovarian cancer cases from high-risk families. PloS one 54 21980511
2011 Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Human mutation 54 21990120
2009 The development of RAD51C, Cystatin A, p53 and Nrf2 luciferase-reporter assays in metabolically competent HepG2 cells for the assessment of mechanism-based genotoxicity and of oxidative stress in the early research phase of drug development. Mutation research 54 20006733
2023 Structure and function of the RAD51B-RAD51C-RAD51D-XRCC2 tumour suppressor. Nature 52 37344587
2004 Human Rad51C deficiency destabilizes XRCC3, impairs recombination, and radiosensitizes S/G2-phase cells. The Journal of biological chemistry 51 15292210
2003 Identification of functional domains in the RAD51L2 (RAD51C) protein and its requirement for gene conversion. The Journal of biological chemistry 46 12966089
2011 Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility. Breast cancer research and treatment 43 21750962
2018 RAD51C/XRCC3 Facilitates Mitochondrial DNA Replication and Maintains Integrity of the Mitochondrial Genome. Molecular and cellular biology 41 29158291
2015 Genetic testing for RAD51C mutations: in the clinic and community. Clinical genetics 38 25470109
2010 Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast cancer research and treatment 36 20697805
2017 Arabidopsis RAD51, RAD51C and XRCC3 proteins form a complex and facilitate RAD51 localization on chromosomes for meiotic recombination. PLoS genetics 35 28562599
2012 Germline RAD51C mutations in ovarian cancer susceptibility. Clinical genetics 34 22725699
2021 Characterization of a RAD51C-silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance. NAR cancer 32 34316715
2014 Enhanced non-homologous end joining contributes toward synthetic lethality of pathological RAD51C mutants with poly (ADP-ribose) polymerase. Carcinogenesis 32 25292178
2023 RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles. Nature communications 31 37488098
2012 The rice RAD51C gene is required for the meiosis of both female and male gametocytes and the DNA repair of somatic cells. Journal of experimental botany 31 22859673
2011 A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families. Breast cancer research and treatment 31 21537932
2024 High-resolution functional mapping of RAD51C by saturation genome editing. Cell 28 39299233
2014 RAD51C germline mutations found in Spanish site-specific breast cancer and breast-ovarian cancer families. Breast cancer research and treatment 28 25086635
2019 Combined Tumor Sequencing and Case-Control Analyses of RAD51C in Breast Cancer. Journal of the National Cancer Institute 27 30949688
2005 Cellular localization of human Rad51C and regulation of ubiquitin-mediated proteolysis of Rad51. Journal of cellular biochemistry 27 16215984
2019 Human RAD51 paralogue RAD51C fosters repair of alkylated DNA by interacting with the ALKBH3 demethylase. Nucleic acids research 26 31642493
2014 Deleterious RAD51C germline mutations rarely predispose to breast and ovarian cancer in Pakistan. Breast cancer research and treatment 26 24800917
2005 The ATPase motif in RAD51D is required for resistance to DNA interstrand crosslinking agents and interaction with RAD51C. Mutagenesis 26 16236763
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2013 RAD51C deletion screening identifies a recurrent gross deletion in breast cancer and ovarian cancer families. Breast cancer research : BCR 24 24359560
2004 XRCC3 ATPase activity is required for normal XRCC3-Rad51C complex dynamics and homologous recombination. The Journal of biological chemistry 23 15037616
2022 Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants. Proceedings of the National Academy of Sciences of the United States of America 21 36099300
2016 Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer. Breast cancer research and treatment 21 26740214
2009 The interaction profile of homologous recombination repair proteins RAD51C, RAD51D and XRCC2 as determined by proteomic analysis. Proteomics 21 19658102
2021 A decade of RAD51C and RAD51D germline variants in cancer. Human mutation 20 34923718
2013 RAD51C--a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC). Oral oncology 20 24315737
2021 Recurrent Mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish Patients with Ovarian Cancer. Cancers 18 33670479
2021 Age of ovarian cancer diagnosis among BRIP1, RAD51C, and RAD51D mutation carriers identified through multi-gene panel testing. Journal of ovarian research 18 33926482
2012 Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing. Breast cancer research and treatment 18 22370629
2009 The ATR-Chk1 pathway plays a role in the generation of centrosome aberrations induced by Rad51C dysfunction. Nucleic acids research 18 19403737
2007 RAD51C (RAD51L2) is involved in maintaining centrosome number in mitosis. Cytogenetic and genome research 18 17268176
2020 Comprehensive Functional Characterization and Clinical Interpretation of 20 Splice-Site Variants of the RAD51C Gene. Cancers 17 33333735
2007 Resolving RAD51C function in late stages of homologous recombination. Cell division 17 17547768
2003 Region and amino acid residues required for Rad51C binding in the human Xrcc3 protein. Nucleic acids research 17 12853621
2017 Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes. British journal of cancer 15 28829762
2012 Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Familial cancer 15 22476429
2017 Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations. Cancer science 14 28796317
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2004 Spontaneous homologous recombination is decreased in Rad51C-deficient hamster cells. DNA repair 14 15336628
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2018 Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). European journal of medical genetics 13 29409816
2017 Pathologic findings in breast, fallopian tube, and ovary specimens in non-BRCA hereditary breast and/or ovarian cancer syndromes: a study of 18 patients with deleterious germline mutations in RAD51C, BARD1, BRIP1, PALB2, MUTYH, or CHEK2. Human pathology 12 28709830
2017 Expanding the FANCO/RAD51C associated phenotype: Cleft lip and palate and lobar holoprosencephaly, two rare findings in Fanconi anemia. European journal of medical genetics 12 29278735
2016 Estrogen induces RAD51C expression and localization to sites of DNA damage. Cell cycle (Georgetown, Tex.) 12 27753535
2001 Sequence, chromosomal location and expression analysis of the murine homologue of human RAD51L2/RAD51C. Gene 12 11410366
2023 Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C. Cancer research 11 37253112
2018 Gene-panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication. Clinical genetics 11 28802053
2013 C. elegans ring finger protein RNF-113 is involved in interstrand DNA crosslink repair and interacts with a RAD51C homolog. PloS one 11 23555887
2023 Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress. Nature communications 10 36906610
2022 Minigene Splicing Assays Identify 20 Spliceogenic Variants of the Breast/Ovarian Cancer Susceptibility Gene RAD51C. Cancers 10 35740625
2021 TAZ maintains telomere length in TNBC cells by mediating Rad51C expression. Breast cancer research : BCR 10 34488828