Gonzalez David I, Westerbeek Allison R, Epum Esther A, Friedman Katherine L
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, US.
bioRxiv. 2025 Jun 28:2025.06.27.661970. doi: 10.1101/2025.06.27.661970.
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 telomere addition (TA), can be utilized. Yeast subtelomeric regions are hotspots of recombination, while interstitial telomere-like sites can promote TA. In yeast, TA sites, termed SiRTAs (Sites of Repair-associated Telomere Addition), require Cdc13 association. We identified the ubiquitin protease Ubp10 as a positive regulator of TA at SiRTAs. Loss of reduces TA frequency but increases the frequency of other chromosomal rearrangements at SiRTAs. SiRTAs utilize the repetitive subtelomeric regions of donor chromosomes to facilitate rearrangements, with a fraction occurring independently of and requiring Sir4 and Sir2 components of the SIR complex. Association of Cdc13 with the SiRTA is necessary and sufficient to stimulate translocations in the absence of . This study highlights the diversity of DNA repair mechanisms at SiRTAs, advancing our understanding of telomere maintenance and chromosomal rearrangement formation.
双链断裂（DSBs）对染色体稳定性构成重大威胁，如果不进行修复，可能导致染色体重排。经典的DNA修复途径可降低这些风险。然而，如果这些修复机制未能修复DSB，就可以利用替代修复途径，如断裂诱导复制（BIR）、单链退火（SSA）和端粒添加（TA）。酵母亚端粒区域是重组热点，而间质端粒样位点可促进TA。在酵母中，称为SiRTAs（修复相关端粒添加位点）的TA位点需要Cdc13结合。我们鉴定出泛素蛋白酶Ubp10是SiRTAs处TA的正调控因子。Ubp10缺失会降低TA频率，但会增加SiRTAs处其他染色体重排的频率。SiRTAs利用供体染色体的重复亚端粒区域促进重排，其中一部分重排独立于Ubp10发生，并且需要SIR复合物的Sir4和Sir2成分。在没有Ubp10的情况下，Cdc13与SiRTA的结合对于刺激易位是必要且充分的。这项研究突出了SiRTAs处DNA修复机制的多样性，增进了我们对端粒维持和染色体重排形成的理解。
