AI Article Synopsis

  • Mutations in homologous recombination (HR) genes, particularly in RAD51C, are linked to increased tumor risk and greater sensitivity to certain cancer treatments.
  • A study examined over 50 RAD51C missense variants and found that certain mutations significantly hindered HR functionality and disrupted connectivity with other RAD51 paralogs.
  • Structural models and analyses indicate that specific mutations affect ATP binding and interactions within RAD51C complexes, while patients with certain RAD51C variants displayed longer survival rates, offering new insights into variant classification and their potential effects on treatment outcomes.

Article Abstract

Mutations in homologous recombination (HR) genes, including , , and the RAD51 paralog , 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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499524PMC
http://dx.doi.org/10.1073/pnas.2202727119DOI Listing

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