The role of the Smc5/6 complex in DNA repair

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Structural maintenance of chromosomes (SMC) proteins function in many aspects of chromosome organization and DNA metabolism processes including repair. The SMC proteins are highly conserved and form ring-like structures that interact with DNA, organizing and restricting its movement. Emphasizing their significance, SMC proteins are conserved in the three phyla of life and their evolutionary emergence predates that of histones. SMC proteins are central to the process of how DNA is systematically packaged after replication and segregated in mitosis. In eukaryotes there are six different SMC proteins forming the core of three distinct heterodimeric complexes including 1. cohesin (Smc1/Smc3), 2. condensin (Smc2/Smc4), and 3. Smc5/6 complex (Smc5/ Smc6). The global pattern of Smc5/6 binding to the genome shows peak enrichment at collapsed replication forks, telomeres, rDNA, and centromeres. In addition, the complex is also recruited to DNA double strand breaks, however its function at sites of damage remains elusive. Within the Smc5/6 complex there are six Non-Smc-Elements (Nse1-6). Recently, we characterized Nse5 and find it has a role in sumoylation reactions. Nse5 has two putative SUMO interacting motifs (SIMs) that when mutated, result in a loss of interaction with SUMO. The broad objective of this proposal is to understand the fundamental dynamics of SMC proteins during DNA damage. More specifically we will use a combination of genetics, biochemical, and microscopy methods to investigate the role of Smc5/6 and sumoylation in the repair of DNA damage. These studies will provide novel insight into the function of the SMC complex for genomic maintenance and the accurate transmission of DNA from mother to daughter cells.