Regulation of Genome Maintenance by Chromatin-Associated Protein Degradation

DNA损伤的积累引起细胞DNA损伤反应，以维持基因组的稳定性。DNA双链断裂（DSBs）是由DNA复制缺陷或基因毒性损伤（如电离辐射、放射性模拟化学物质或活性氧）引起的。有趣的是，随后的DDR诱导受到泛素修饰的严格调控。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，与其在蛋白质质量控制中的良好功能相比，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在染色质相关过程中的分子作用，这些过程对DNA代谢和基因组监测很重要。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串扰提供新的见解。

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.