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    Understanding the regulation of telomere healing in S. cerevisiae: a Rad51 perspective.

    EPUM, ESTHER AKUNNA
    : https://etd.library.vanderbilt.edu/etd-09152019-201701
    http://hdl.handle.net/1803/14152
    : 2019-09-16

    Abstract

    DNA double-strand breaks (DSBs) are toxic forms of DNA damage that must be repaired to maintain genome integrity. In addition to maintaining telomeres, telomerase can act on DSBs creating de novo telomeres, a mutagenic process associated with 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 telomere-binding protein Cdc13 with a SiRTA is required to stimulate de novo telomere addition. Here, my work shows that telomere addition is reduced significantly in the absence of RAD51 but not RAD52 at two SiRTAs. RAD52 deletion completely suppresses the telomere addition defect associated with RAD51 deletion, suggesting that Rad51 counteracts the inhibitory activity of Rad52. This work showed that a Rad51 mutant, impaired in nucleofilament formation and single-strand DNA binding, is nevertheless competent for telomere formation. In contrast, a Rad51 mutant, defective in interaction with Rad52, is deficient in telomere formation similar to a C-terminal truncation mutant of Rad52, impaired in its interaction with Rad51. Remarkably, Rad51 mutations decreasing telomere formation at SiRTAs also lead to an increase in Rad52-dependent microhomology-mediated repair(MHMR) internal to the SiRTA on chromosome IX. Finally, my work shows that a Rfa1 mutant, rfa1-44, reduced in its ability to interact with Rad52, also suppresses the telomere addition defect of RAD51 deletion. This work suggests that in the absence of Rad51, Rad52 interacts with RFA1 in a manner that inhibits telomere formation at SiRTAs and result in increased MHMR events.
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