Regulation of Genome Maintenance by Chromatin-Associated Protein Degradation

通过染色质相关蛋白降解调节基因组维护

• 批准号: 236832596
• 负责人: Professor Dr. Thorsten Hoppe
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/236832596?language=en
• 关键词: Regulation; Genome; Maintenance; Chromatin; Associated

Accumulation of DNA lesions causes the induction of the cellular DNA damage response to maintain genome stability. DNA double-strand breaks (DSBs) result from defects in DNA replication or genotoxic insults such as ionizing radiation, radiomimetic chemicals, or reactive oxygen species. Interestingly, the subsequent induction of the DDR is tightly regulated by ubiquitin modification. Our recent work revealed a central role of the ubiquitin-selective chaperone CDC-48/p97 in DNA replication and DSB repair, regulating the activity and turnover of ubiquitylated proteins bound to chromatin. However, in contrast to its well-established function in protein quality control, the mechanistic role of CDC-48/p97 in chromatin-associated protein degradation and genome maintenance is unclear. The central objective of our proposed research is to define the molecular role of CDC-48/p97 in chromatin-associated processes important for DNA metabolism and genome surveillance. Given its key activity as a ubiquitin-selective segregase, understanding how CDC-48/p97 regulates cell cycle progression and DNA repair would provide novel insights into the cross talk between ubiquitin, genome stability, and cancer development.

DNA损伤的积累引起细胞DNA损伤反应的诱导以维持基因组稳定性。DNA双链断裂（DSB）是由DNA复制缺陷或遗传毒性损伤（如电离辐射、拟辐射化学物质或活性氧）引起的。有趣的是，随后的DDR诱导是由泛素修饰严格调控。我们最近的工作揭示了泛素选择性伴侣CDC-48/p97在DNA复制和DSB修复中的核心作用，调节与染色质结合的泛素化蛋白的活性和周转。然而，与CDC-48/p97在蛋白质质量控制中的公认功能相反，CDC-48/p97在染色质相关蛋白质降解和基因组维持中的机制作用尚不清楚。我们提出的研究的中心目标是确定CDC-48/p97在DNA代谢和基因组监测重要的染色质相关过程中的分子作用。鉴于其作为泛素选择性分离酶的关键活性，了解CDC-48/p97如何调节细胞周期进程和DNA修复将为泛素，基因组稳定性和癌症发展之间的相互作用提供新的见解。