Studies of the Smc5/Smc6 complex in chromosomal replication

描述（由申请人提供）：癌症和其他人类疾病中出现的许多染色体异常和遗传不稳定性是由染色体复制缺陷引起的。染色体复制不仅需要基本复制机制的适当功能，而且还需要科普模板上的染色质和损伤的复杂性质的能力，这两者都可能导致复制叉停滞或崩溃。检查点途径已被证明在调解促进恢复和完成复制的多个措施中发挥关键作用。此外，能够协调染色体行为和基本DNA复制程序的特殊机制也至关重要。SMC（染色体结构维持）蛋白及其复合物，包括新表征的Smc 5/6复合物，是动态分子连接物，可以主动系链和折叠染色单体，从而提供染色体结构和复制程序之间的重要连接。我们的长期目标是了解染色体复制中使用的特殊程序。在本资助期内，我们将重点研究Smc 5/6复合体在复制中的功能。我们发现Smc 5/6复合物在染色体复制中起着多种作用，其中一些作用是由其SUMO E3亚基Mms 21介导的。使用遗传学，细胞生物学和生物化学方法的组合，我们将研究Smc 5/6复合物调节染色体复制的机制。在具体的目标之一，我们将确定Smc 5/6复合物如何抵消在受损的复制叉的重组事件。在具体的目标二，我们将研究额外的功能的Smc 5/6复合物在复制和探针之间的物理相互作用的Smc 5/6复合物和蛋白质复制的重要性。这两个目标的结合结果将为复制，染色体动力学和重组修复之间的关系提供新的见解。它可能有助于理解人类Smc 5/6复合物的功能，并可能导致与癌症和其他人类疾病相关的基因组不稳定性的方法。由于染色质和核组织的复杂性，染色体复制面临许多挑战。因此，它需要特殊的机制来协调染色体行为和基本的DNA复制和修复程序。在这些过程的界面上进化保守的Smc 5/6复杂功能。我们描述的研究计划，以解决机制，这种复杂的共调节不同的途径在染色体复制。这些研究的结果将为这些基本过程提供新的见解，并将揭示与这些过程中的缺陷相关的人类疾病的原因和治疗。

DESCRIPTION (provided by applicant): Many chromosomal abnormalities and genetic instability arising in cancer and other human diseases are caused by defects in chromosomal replication. Chromosomal replication not only requires the proper function of the basic replication machinery, but also demands an ability to cope with the complex nature of chromatin and lesions on the template, both of which can lead to replication fork stalling or collapse. Checkpoint pathways have been shown to play key roles in mediating multiple measures that promote the recovery and completion of replication. In addition, special mechanisms that can coordinate chromosomal behavior and basic DNA replication programs are critical. SMC (structural maintenance of chromosome) proteins and their complexes, including the newly characterized Smc5/6 complex, are dynamic molecular linkers that can actively tether and fold chromatids, thereby providing important connections between chromosomal structures and replication programs. Our long-term goal is to understand the special programs utilized in chromosomal replication. In this grant period, we will focus on functions of the Smc5/6 complex in replication. We showed that the Smc5/6 complex plays multiple roles in chromosomal replication and some of its roles are mediated by its SUMO E3 subunit Mms21. Using a combination of genetic, cell biological, and biochemical approaches, we will study the mechanisms by which the Smc5/6 complex regulates chromosomal replication. In specific aim one, we will determine how the Smc5/6 complex counteracts recombinogenic events at damaged replication forks. In specific aim two, we will study the additional functions of the Smc5/6 complex in replication and probe for physical interactions between the Smc5/6 complex and proteins important for replication. The combined results from these two aims will provide new insights into the relationship between replication, chromosomal dynamics and recombinational repair. It will likely contribute to the understanding of the functions of the human Smc5/6 complex and potentially lead to methods to battle genomic instability associated with cancer and other human diseases. Chromosomal replication faces many challenges posed by the complex nature of chromatin and nuclear organization. It therefore requires special mechanisms that coordinate chromosomal behavior and basic DNA replication and repair programs. The evolutionarily conserved Smc5/6 complex functions at the interface of these processes. We describe research programs to address the mechanisms by which this complex co- regulates different pathways during chromosomal replication. Results from these studies will provide new insights into these fundamental processes and will shed lights on the cause and treatment of human diseases related to defects in these processes.