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Emerging non-canonical roles for the Rad51-Rad52 interaction in response to double-strand breaks in yeast.

ABSTRACT: DNA double-strand break repair allows cells to survive both exogenous and endogenous insults to the genome. In yeast, the recombinases Rad51 and Rad52 are central to multiple forms of homology-dependent repair. Classically, Rad51 and Rad52 are thought to act cooperatively, with formation of the functional Rad51 nucleofilament facilitated by the mediator function of Rad52. Several studies have now identified functions for the interaction between Rad51 and Rad52 that are independent of the mediator function of Rad52 and affect a seemingly diverse array of functions in de novo telomere addition, global chromosome mobility following DNA damage, Rad51 nucleofilament stability, checkpoint adaptation, and microhomology-mediated chromosome rearrangements. Here, we review these functions with an emphasis on our recent discovery that the Rad51-Rad52 interaction influences the probability of de novo telomere addition at sites preferentially targeted by telomerase following a double-strand break (DSB). We present data addressing the prevalence of sites within the yeast genome that are capable of stimulating de novo telomere addition following a DSB and speculate about the potential role such sites may play in genome stability.

SUBMITTER: Ngo K

PROVIDER: S-EPMC7492393 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:DNA double-strand breaks (DSBs) are toxic forms of DNA damage that must be repaired to maintain genome integrity. Telomerase can act upon a DSB to create a de novo telomere, a process that interferes with normal repair and creates terminal deletions. We previously identified sequences in Saccharomyces cerevisiae (SiRTAs; Sites of Repair-associated Telomere Addition) that undergo unusually high frequencies of de novo telomere addition, even when the original chromosome break is several kilobases distal to the eventual site of telomerase action. Association of the single-stranded telomere binding protein Cdc13 with a SiRTA is required to stimulate de novo telomere addition. Because extensive resection must occur prior to Cdc13 binding, we utilized these sites to monitor the effect of proteins involved in homologous recombination. We find that telomere addition is significantly reduced in the absence of the Rad51 recombinase, while loss of Rad52, required for Rad51 nucleoprotein filament formation, has no effect. Deletion of RAD52 suppresses the defect of the rad51Δ strain, suggesting that Rad52 inhibits de novo telomere addition in the absence of Rad51. The ability of Rad51 to counteract this effect of Rad52 does not require DNA binding by Rad51, but does require interaction between the two proteins, while the inhibitory effect of Rad52 depends on its interaction with Replication Protein A (RPA). Intriguingly, the genetic interactions we report between RAD51 and RAD52 are similar to those previously observed in the context of checkpoint adaptation. Forced recruitment of Cdc13 fully restores telomere addition in the absence of Rad51, suggesting that Rad52, through its interaction with RPA-coated single-stranded DNA, inhibits the ability of Cdc13 to bind and stimulate telomere addition. Loss of the Rad51-Rad52 interaction also stimulates a subset of Rad52-dependent microhomology-mediated repair (MHMR) events, consistent with the known ability of Rad51 to prevent single-strand annealing.

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Emerging non-canonical roles for the Rad51-Rad52 interaction in response to double-strand breaks in yeast.

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