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Ref Type Journal Article
PMID (36562461)
Authors Kolinjivadi AM, Chong ST, Choudhary R, Sankar H, Chew EL, Yeo C, Chan SH, Ngeow J
Title Functional analysis of germline RAD51C missense variants highlight the role of RAD51C in replication fork protection.
Journal Vol Issue Date Pages Journal Short Title
Human molecular genetics 32 8 2023 Apr 06 1401-1409 Hum Mol Genet
URL
Abstract Text Monoallelic or biallelic RAD51C germline mutations results in chromosome instability disorders such as Fanconi anemia and cancers. The bona fide function of RAD51C is to assist RAD51 nucleoprotein filament onto single-strand DNA to complete homologous recombination (HR) repair. In addition to HR repair, the role of RAD51C in DNA replication is emerging when replication forks are transiently or irreversibly stalled. We identified novel RAD51C variants of uncertain significance (VUS) from breast, ovarian, pancreatic and gastric cancer patients and functionally characterized the effect of these variants in replication fork protection and double-strand breaks (DSB's) repair. In RAD51C-deficient Chinese hamster CL-V4B cells, expression of RAD51C F164S, A87E, L134S and E49K variants heightened sensitivity to mitomycin C (MMC), etoposide and PARP inhibition. Differently, expression of subset of RAD51C variants R24L, R24W and R212H displayed mild sensitivity to MMC, etoposide and PARP inhibition. Further functional characterization of a subset of variants revealed that Rad51C F164S, A87E, L134S and E49K variants displayed reduced RAD51 foci formation and increased overall nuclear single strand DNA levels in the presence of replication stress. Additionally, DNA fiber assay revealed that RAD51C F164S, A87E, L134S and E49K variants displayed defective replication fork protection upon prolonged fork stalling. Investigations using patient-derived lymphoblastoid cell line carrying heterozygous RAD51C L134S variant showed an impairment in RAD51 chromatin association and replication fork protection, suggestive of deleteriousness of this VUS variant. Overall, our findings provide more insights into molecular roles of RAD51C in replication fork integrity maintenance and in DSB repair.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
RAD51C A87E missense loss of function RAD51C A87E lies within a region of the Rad51c protein required for Holliday junction resolution activity and the RAD51B, RAD51D, and XRCC3-interacting region of the Rad51c protein (UniProt.org). A87E confers a loss of function to Rad51c as demonstrated by impaired ability to rescue survival of RAD51C-deficient cells upon treatment with mitomycin c, topoisomerase II and PARP inhibitors, and hydroxyurea, increased levels of single strand DNA, reduced Rad51 foci formation, defective replication fork protection, and increased chromosome breaks in culture (PMID: 36562461), and decreased survival in a high-throughput cell culture assay (PMID: 39299233).
RAD51C E49K missense loss of function - predicted RAD51C E49K lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). E49K demonstrates a partial reduction in the ability to rescue survival of RAD51C-deficient cells upon treatment with mitomycin c, topoisomerase II and PARP inhibitors, and hydroxyurea, reduced Rad51 foci formation, defective replication fork protection, increased levels of single strand DNA, and increased chromosome breaks in culture (PMID: 36562461), and decreased survival in a high-throughput cell culture assay (PMID: 39299233), and therefore, is predicted to lead to a loss of Rad51c protein function.
RAD51C F164S missense loss of function RAD51C F164S does not lie within any known functional domains of the Rad51c protein (UniProt.org). F164S confers a loss of function to Rad51c as demonstrated by impaired ability to rescue survival of RAD51C-deficient cells upon treatment with mitomycin c, topoisomerase II and PARP inhibitors, and hydroxyurea, increased levels of single strand DNA, reduced Rad51 foci formation, defective replication fork protection, and increased chromosome breaks in culture (PMID: 36562461), and decreased survival in a high-throughput cell culture assay (PMID: 39299233).
RAD51C L134S missense loss of function - predicted RAD51C L134S lies within the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). L134S demonstrates a partial reduction in the ability to rescue survival of RAD51C-deficient cells upon mitomycin c and PARP inhibitors treatment, reduced Rad51 foci formation in cell culture, a modest increase in sensitivity to topoisomerase II inhibitors and hydroxyurea, defective replication fork protection, and increased chromosome breaks in patient cells and in cultured cells (PMID: 36562461), and decreased survival in a high-throughput cell culture assay (PMID: 39299233), and therefore, is predicted to lead to a loss of Rad51c protein function.
RAD51C R24L missense unknown RAD51C R24L lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). R24L maintains functional homology-directed DNA repair activity in cell culture (PMID: 37253112), and retains the ability to complement hypersensitivity to mitomycin C and etoposide in RAD51C-deficient cells, but demonstrates impaired ability to rescue survival of RAD51C-deficient cells upon PARP inhibitor treatment in culture (PMID: 36562461), and results in decreased survival in a high-throughput cell culture assay (PMID: 39299233), and therefore, its effect on Rad51c protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RAD51C L134S Advanced Solid Tumor predicted - sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, Talzenna (talazoparib) moderately inhibited proliferation of cells expressing RAD51C L134S in culture (PMID: 36562461). 36562461
RAD51C A87E Advanced Solid Tumor sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, Talzenna (talazoparib) inhibited proliferation of cells expressing RAD51C A87E in culture (PMID: 36562461). 36562461
RAD51C F164S Advanced Solid Tumor sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, Talzenna (talazoparib) inhibited proliferation of cells expressing RAD51C F164S in culture (PMID: 36562461). 36562461
RAD51C E49K Advanced Solid Tumor sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, Talzenna (talazoparib) inhibited proliferation of cells expressing RAD51C E49K in culture (PMID: 36562461). 36562461