Loss of the RAD-51 isoform A redirects DNA repair and preserves genome stability in FANCD2-deficient Caenorhabditis elegans.

Abstract

Background: Fanconi anemia is a rare genomic instability syndrome associated with congenital abnormalities and cancer predisposition. These alterations are mainly due to deficiencies in DNA repair mechanisms. The Fanconi anemia pathway is evolutionarily conserved, allowing functional studies in model organisms like Caenorhabditis elegans, where it promotes and executes error-free homologous-recombination over the mutagenic non-homologous-end-joining pathway; fcd-2 (FANCD2 ortholog) plays a key role in this regulation to preserve genome stability. In this study, we report that the choice of DNA repair pathway for resolving double-strand breaks is influenced by absence of the RAD-51 long isoform, a key component of the Fanconi anemia pathway that plays a central role in homologous strand exchange during recombination.

Results: In C. elegans, which is predicted to encode three RAD-51 isoforms, we find that loss of RAD-51 isoform A enhances homologous recombination efficiency. Additionally, RAD-51 isoform A depletion decreases developmental and meiotic defects in fcd-2 mutants as well as reduces chromosome aggregation in fcd-2-deficient germ cells.

Conclusions: Together, these findings reveal a novel role for RAD-51 C. elegans, suggesting that the pattern of RAD-51 isoform expression modulates the balance between homologous recombination and non-homologous-end-joining, thereby preserving genome stability.