Homologous recombination–deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants Journal Article
| Authors: | Prakash, R.; Rawal, Y.; Sullivan, M. R.; Grundy, M. K.; Bret, H.; Mihalevic, M. J.; Rein, H. L.; Baird, J. M.; Darrah, K.; Zhang, F.; Wang, R.; Traina, T. A.; Radke, M. R.; Kaufmann, S. H.; Swisher, E. M.; Guérois, R.; Modesti, M.; Sung, P.; Jasin, M.; Bernstein, K. A. |
| Article Title: | Homologous recombination–deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants |
| Abstract: | Mutations in homologous recombination (HR) genes, including BRCA1, BRCA2, and the RAD51 paralog RAD51C, predispose to tumorigenesis and sensitize cancers to DNA-damaging agents and poly(ADP ribose) polymerase inhibitors. However, ∼800 missense variants of unknown significance have been identified for RAD51C alone, impairing cancer risk assessment and therapeutic strategies. Here, we interrogated >50 RAD51C missense variants, finding that mutations in residues conserved with RAD51 strongly predicted HR deficiency and disrupted interactions with other RAD51 paralogs. A cluster of mutations was identified in and around the Walker A box that led to impairments in HR, interactions with three other RAD51 paralogs, binding to single-stranded DNA, and ATP hydrolysis. We generated structural models of the two RAD51 paralog complexes containing RAD51C, RAD51B-RAD51C-RAD51D-XRCC2 and RAD51C-XRCC3. Together with our functional and biochemical analyses, the structural models predict ATP binding at the interface of RAD51C interactions with other RAD51 paralogs, similar to interactions between monomers in RAD51 filaments, and explain the failure of RAD51C variants in binding multiple paralogs. Ovarian cancer patients with variants in this cluster showed exceptionally long survival, which may be relevant to the reversion potential of the variants. This comprehensive analysis provides a framework for RAD51C variant classification. Importantly, it also provides insight into the functioning of the RAD51 paralog complexes. Copyright © 2022 the Author(s). Published by PNAS. |
| Keywords: | controlled study; dna binding protein; gene cluster; gene mutation; human cell; genetics; mutation; dna-binding proteins; ovarian neoplasms; cell viability; gene; homologous recombination; cell survival; dna repair; ovary cancer; gene locus; genetic association; genetic variability; prediction; homozygosity; amino terminal sequence; algorithm; gene interaction; gene identification; ovary tumor; scoring system; adenosine triphosphate; single stranded dna; gel mobility shift assay; rad51 protein; rad51 recombinase; rad51c gene; dna sequencing; humans; human; female; article; rad51c; rad51 paralog; variants of unknown significance; rad51c protein, human; xrcc2 protein, human |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 119 |
| Issue: | 38 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2022-09-20 |
| Start Page: | e2202727119 |
| Language: | English |
| DOI: | 10.1073/pnas.2202727119 |
| PUBMED: | 36099300 |
| PROVIDER: | scopus |
| PMCID: | PMC9499524 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
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