The role of the Smc5/6 complex in nuclear organization

Smc5/6复合物在核组织中的作用

• 批准号: RGPIN-2017-04830
• 负责人: Cobb, Jennifer
• 金额: $ 2.91万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744254
• 关键词: role; Smc5; complex; nuclear; organization

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.

染色体结构维持（SMC）蛋白形成环状结构，与基因组相互作用以组织和限制其运动。在真核生物中，有六种不同的SMC蛋白形成三种不同的异二聚体复合物的核心，包括1。粘附素（Smc 1/Smc 3），2.冷凝（Smc 2/Smc 4），和3. Smc 5/6复合体（Smc 5/Smc 6）。SMC蛋白复合物是DNA系统包装过程的核心。在复制后，凝聚素调节姐妹染色单体的凝聚，而在细胞进入有丝分裂时，凝聚素驱动染色体包装和凝聚。相比之下，Smc 5/6的大部分工作主要是在同源重组（HR）和DNA修复的背景下进行的。我们实验室最近的新工作表明，Smc 5/6也具有与核周边染色质相关的功能，并在端粒处维持高阶染色质结构。 染色体在细胞核中排列，并定位于特定的位置。 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。核周边是抑制重组的区域。凝聚素和凝聚素参与了细胞核的空间组织，然而Smc 5/6在细胞核组织中的作用还没有得到解决。 这是令人惊讶的，因为Smc 5/6结合到基因组中的重复序列，包括端粒和定位于核周边的rDNA。 Smc 5/6在染色质周围的特性将提供一个更清晰的理解，如何复杂的功能，下调不适当的同源recombinations.Our中心假设：Smc 5/6绑定重复元件，如端粒和rDNA定位到核周边通过与内核膜（INM）蛋白的相互作用。 我们目前的提案目标包括：目标1：确定Smc 5/6是否在外周系留端粒中发挥作用。 我们将确定Smc 5/6是否对端粒相互作用和Mps 3的束缚很重要。目的2：研究Smc 5/6在rDNA外周系链中的作用。我们将确定Smc 5/6在rDNA的定位是否对Heh 1和Nur 1的重复元件的拴系很重要。