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Cellular and Pathological Responses to Chromosome DNA Single-Strand Breaks

对染色体 DNA 单链断裂的细胞和病理反应

基本信息

批准号：
MR/P010121/1
负责人：
Keith Caldecott
金额：
$ 258.03万
依托单位：
University of Sussex
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP010121%2F1
关键词：
Cellular Pathological Responses Chromosome DNA

项目摘要

My laboratory is focused on understanding how breaks in the genetic material (DNA) can lead to neurodegeneration. The proposed work will address exciting new hypotheses that have arisen during my current research Programme concerning the mechanism/s by which DNA single-strand breaks are sensed and repaired, and exciting and unexpected novel physiological roles for the pathway that repairs these breaks (single-strand break repair). We have also uncovered a mechanism by which unrepaired single-strand breaks trigger neurodegeneration, providing not only the first molecular explanation of this pathological event but also opening up possible avenues for therapeutic intervention. We plan to pursue these novel discoveries in the new Programme of work proposed here. Whilst we are focusing on experimental models of rare genetic diseases to address our scientific questions, the relevance of this work may extend to degenerative diseases observed in the normal ageing population. This is because single-strand breaks are the commonest DNA lesions arising in cells and are induced by oxidative stress; an etiological factor implicated in ageing.

我的实验室专注于了解遗传物质（DNA）的断裂如何导致神经变性。这项工作将解决在我目前的研究计划中出现的令人兴奋的新假设，这些假设涉及DNA单链断裂被感知和修复的机制，以及修复这些断裂的途径（单链断裂修复）令人兴奋和意想不到的新生理作用。我们还发现了未修复的单链断裂触发神经退行性变的机制，不仅提供了这种病理事件的第一个分子解释，而且为治疗干预开辟了可能的途径。我们计划在这里提出的新的工作纲领中继续进行这些新的发现。虽然我们专注于罕见遗传疾病的实验模型来解决我们的科学问题，但这项工作的相关性可能会扩展到在正常老龄化人口中观察到的退行性疾病。这是因为单链断裂是细胞中最常见的DNA损伤，是由氧化应激引起的；与衰老有关的病因因素。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.

DOI：
10.1016/j.molcel.2021.05.009
发表时间：
2021-07-15
期刊：
Molecular cell
影响因子：
16
作者：
Demin AA;Hirota K;Tsuda M;Adamowicz M;Hailstone R;Brazina J;Gittens W;Kalasova I;Shao Z;Zha S;Sasanuma H;Hanzlikova H;Takeda S;Caldecott KW
通讯作者：
Caldecott KW

Overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin.