The regulation of Mre11-Rad50-Nbs1 (MRN) complex disassembly in response to ionising radiation.

Mre11-Rad50-Nbs1 (MRN) 复合物分解响应电离辐射的调节。

• 批准号: 2744488
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2744488
• 关键词: regulation; Mre11; Rad50; Nbs1; MRN

The complex formed by MRE11 -RAD50 and -NBS1, designated the MRN complex, has a well-defined role in homologous recombination, a DNA repair pathway that repairs double-strand breaks (DSBs). There is mechanistic detail regarding how the MRN complex is recruited to the sites of DSBs and how it completes its physiological role although it is not known how the MRN complex is disassembled from DBSs. Recent evidence suggests that the AAA+ ATPase p97 has a role in extracting the MRN complex from chromatin. Without this segregase or unfoldase, MRE11 accumulates on chromatin and genome instability ensues. I aim to understand the mechanistic details of how p97 removes the MRN complex from chromatin. The MRN complex and p97 are associated with cancer formation and advanced cancers. Furthermore, they have been suggested as cancer therapy targets, as sole therapies or in combination with other therapies, inducing synthetic lethality e.g., radiosensitisers. There are ongoing clinical trials targeting both of these agents (NCT03921021 and NCT04402541).

由MRE 11-RAD 50和-NBS 1形成的复合物，称为MRN复合物，在同源重组中具有明确的作用，同源重组是一种修复双链断裂（DSB）的DNA修复途径。关于MRN复合物如何被募集到DSB的位点以及它如何完成其生理作用，存在机制细节，尽管尚不知道MRN复合物如何从DBS中分解。最近的证据表明AAA+ ATP酶p97在从染色质中提取MRN复合物中起作用。没有这种分离酶或解折叠酶，MRE 11在染色质上积累，基因组不稳定性增强。我的目标是了解p97如何从染色质中去除MRN复合物的机制细节。MRN复合物和p97与癌症形成和晚期癌症相关。此外，它们已被建议作为癌症治疗靶点，作为单一疗法或与其他疗法组合，诱导合成致死性，放射增敏剂。针对这两种药物的临床试验正在进行中（NCT 03921021和NCT 04402541）。