The role of the Smc5/6 complex in nuclear organization

染色体的结构维持(SMC)蛋白形成环状结构，与基因组相互作用，组织和限制其运动。在真核生物中，有六种不同的SMC蛋白构成了三个不同的异二聚体复合体的核心，包括1.粘附素(Smc1/Smc3)，2.凝集素(Smc2/Smc4)和3.Smc5/6复合体(Smc5/Smc6)。SMC蛋白质复合体是DNA系统包装过程的核心。粘附素调节复制后姐妹染色单体的凝聚力，当细胞进入有丝分裂时，凝集素驱动染色体的包装和凝聚。相反，大多数关于Smc5/6的工作主要是在同源重组(HR)和DNA修复的背景下进行的。我们实验室最近的研究表明，Smc5/6还在染色质与核外周结合以及维持端粒的高阶染色质结构方面具有功能。*染色体在细胞核中被组织起来，并定位到首选位置。核膜在这一过程中起着核心作用，对维持基因组的结构至关重要。核周是重组的抑制区域。粘附素和凝聚素参与了核的空间组织，但Smc5/6在核组织中的作用尚未得到解决。这很令人惊讶，因为Smc5/6结合了基因组中的重复序列，包括端粒和定位于核外围的rDNA。Smc5/6在外围连接染色质的特征将为更清楚地理解该复合体如何下调不适当的同源重组。*我们的中心假设：Smc5/6通过与内核膜(INM)蛋白相互作用，结合端粒和rDNA等重复元件，将它们定位于核外周。我们当前提案的目标包括：*目标1：确定Smc5/6是否在连接端粒的外围起作用。我们将确定Smc5/6是否对端粒相互作用和与Mps3的拴系重要。*目标2：研究Smc5/6在连接外周rDNA中的作用。我们将确定Smc5/6在rDNA上的定位是否对于将重复元件拴在Heh1和Nur1上是重要的。**

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. **