The ubiquitin protease Ubp10 suppresses the formation of subtelomeric rearrangements at interstitial Cdc13 binding sites in Saccharomyces cerevisiae

Abstract

Double strand breaks (DSBs) pose a significant threat to chromosome stability and, if left unrepaired, can result in chromosome rearrangements. Canonical DNA repair pathways mitigate these risks. However, if these repair mechanisms fail to repair the DSB, alternative repair pathways, such as break-induced replication (BIR), single-strand annealing (SSA), and de novo telomere addition (dnTA), can be utilized. Yeast subtelomeric regions are hotspots of recombination, while interstitial telomere-like sites can promote dnTA. In yeast, dnTA sites, termed SiRTAs (Sites of Repair-associated Telomere Addition), require Cdc13 association. We identified the ubiquitin protease Ubp10 as a positive regulator of dnTA at SiRTAs. Loss of UBP10 reduces dnTA frequency but increases the frequency of subtelomeric rearrangements at SiRTAs. Cdc13 association with the SiRTA is necessary and sufficient to stimulate translocations in the absence of UBP10. Translocations at the SiRTA are likely facilitated by the accumulation of ubiquitinated PCNA, which in turn promotes DNA damage tolerance pathways. The work in this thesis highlights the diversity of DNA repair mechanisms at interstitial telomere-like sites (SiRTAs), advancing our understanding of telomere maintenance and chromosomal rearrangement formation.