The role of the Smc5/6 complex in nuclear organization

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Structural maintenance of chromosomes (SMC) proteins form ring-like structures that interact with the genome to organize and restrict its movement. 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. The Smc5/6 complex (Smc5/Smc6). SMC protein complexes are central to the process of how DNA is systematically packaged. Cohesin regulates sister chromatid cohesion after replication and condensin drives chromosome packaging and condensation as cells go into mitosis. In contrast, most work on Smc5/6 has been primarily performed in the context of homologous recombination (HR) and DNA repair. Emerging work from our lab recently showed that Smc5/6 also has a function in chromatin association with the nuclear periphery and in maintaining higher-order chromatin structure at telomeres. Chromosomes are organized in the nucleus and locate to preferred positions. The nuclear envelope has a central role in this process and is critical for maintaining the architecture of the genome. The nuclear periphery is a region inhibitory to recombination. Cohesin and condensin are involved in the spatial organization of the nucleus, however a role for Smc5/6 in nuclear organization has not been addressed. This is surprising because Smc5/6 binds to repeats in the genome including telomeres and the rDNA that localize to the nuclear periphery. Characterization of Smc5/6 in tethering chromatin at the periphery will provide a clearer understanding of how the complex functions to down-regulate inappropriate homologous recombination.Our central hypothesis: Smc5/6 binds repetitive elements such as telomeres and the rDNA localizing them to the nuclear periphery through interactions with inner nuclear membrane (INM) proteins. Our objectives for the current proposal include: Objective 1: Determine whether Smc5/6 has a role in tethering telomeres at the periphery. We will determine whether Smc5/6 is important for telomere interactions and tethering to Mps3. Objective 2: Examine the role of Smc5/6 in tethering the rDNA at the periphery. We will determine whether the localization of Smc5/6 at the rDNA is important for tethering repetitive elements to Heh1 and Nur1.