Analysis of yeast SUMO ligase MMS21‐dependent genome maintenance pathway (925.4)

Abstract

Genome instability often characterizes many cancers and is indicative of high frequency of mutations and genome rearrangements. Several pathways, including the DNA damage checkpoint, play a role in maintaining the stability of the genome by suppressing gross chromosomal rearrangements (GCRs). Additionally, eukaryotic genomes contain numerous repetitive sequences, segmental duplications and regions of copy number variation, which influence the outcomes of gross chromosomal rearrangements.Using a genetic assay in Saccharomyces cerevisiae to screen for suppressors of GCRs, we recently reported that Mms21‐dependent sumoylation specifically suppress GCRs mediated by homeologous sequences. These types of duplication‐mediated GCRs are attributed to Rad52‐dependent non‐allelic homologous recombination (NAHR). We will present findings that show unexpectedly, the DNA damage checkpoint to be required for the formation of duplication‐mediated GCRs in the absence of Mms21‐dependent sumoylation. The canonical DNA damage checkpoint genes MEC1, RAD24, MEC3, RAD9 and RAD53 are required for formation of duplication‐mediated GCRs in the mms21 mutant, while TEL1, MRC1 and CHK1 are minimally involved. Among the checkpoint genes, mutation of RAD9 strongly suppresses GCRs formed in the mms21 mutant and this suppression is independent of either SIZ1 or SIZ2, which encode two other SUMO ligases in yeast. We will also present findings on the role of DNA damage checkpoint in regulating the SUMO proteome. These results show that the outcomes of GCRs are dynamic and are governed by a fine balance of distinct genome maintenance pathways.Grant Funding Source: GM080469, T32CA009523 ,LICR