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Chromosomal Single-Strand Break Repair: Mechanisms and Degenerative Disease

染色体单链断裂修复：机制和退行性疾病

基本信息

批准号：
MR/J006750/1
负责人：
Keith Caldecott
金额：
$ 266.12万
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：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ006750%2F1
关键词：
Chromosomal Single Strand Break Repair

项目摘要

Breaks in the genetic material (DNA) can lead to a variety of hereditary and age-related diseases, including cancer and neurodegeneration. Whilst the causal link between DNA breaks and cancer is quite well understood, the causal link between DNA breaks and degeneration of the nervous system is not. The aim of the proposed programme is to address critical unanswered questions and new hypotheses concerning the mechanism/s by which breaks in a single strand of DNA (DNA single-strand breaks) are repaired, and the link between this process and degenerative disease. Understanding how DNA single-strand breaks can cause neurodegeneration is important not only for understanding hereditary diseases associated with neurological dysfunction (and hopefully in future for treating and managing such diseases), but most likely also for understanding degenerative diseases associated with normal ageing. This is because DNA single-strand breaks are the commonest lesions arising in cells and are a product of oxidative stress, which in turn is a major etiological factor in pathologies associated with ageing. Indeed, our recent experiments reveal that loss of the critical DNA single-strand break repair protein XRCC1 results in premature onset of molecular and pathological hallmarks of ageing and, moreover, that un-repaired DNA damage in the brain can trigger these hallmarks, systemically (i.e. in undamaged tissues). In addition, we have identified molecular links between the DNA damage response and the hereditary neurodegenerative disease ataxia oculomotor apraxia-2, which we propose identifies a new component of the cellular control of gene expression in the presence of DNA lesions and can explain the basis of this disease. We will now pursue our recent novel findings and hypotheses in this research Programme. In particular, we will address critical questions concerning the organisation and importance of DNA single-strand break repair in vivo, focussing on a novel unidentified role for XRCC1 and on the mechanism by which this protein is recruited at single-strand breaks, and on how DNA single-strand break repair impacts on hereditary and ageing-related degenerative disease. Ultimately, we envisage this work will identify new avenues for treatment & management of degenerative diseases that are associated, wholly or partly, with DNA breakage.

遗传物质（DNA）的断裂会导致各种遗传性和与年龄有关的疾病，包括癌症和神经退行性疾病。虽然DNA断裂和癌症之间的因果关系已经被很好地理解，但DNA断裂和神经系统退化之间的因果关系还没有。拟议方案的目的是解决关键的未回答的问题和新的假设有关的机制/s的断裂在DNA的单链（DNA单链断裂）被修复，这一过程和退行性疾病之间的联系。了解DNA单链断裂如何导致神经退行性变不仅对了解与神经功能障碍相关的遗传性疾病（希望将来能治疗和管理此类疾病）很重要，而且很可能对了解与正常衰老相关的退行性疾病也很重要。这是因为DNA单链断裂是细胞中最常见的病变，是氧化应激的产物，而氧化应激又是与衰老相关的病理学的主要病因。事实上，我们最近的实验表明，关键的DNA单链断裂修复蛋白XRCC 1的丢失会导致衰老的分子和病理学标志的过早发生，此外，大脑中未修复的DNA损伤可以全身性地触发这些标志（即在未受损的组织中）。此外，我们已经确定了DNA损伤反应和遗传性神经退行性疾病共济失调眼用不能-2之间的分子联系，我们建议确定一个新的组成部分的细胞控制基因表达的DNA损伤的存在下，可以解释这种疾病的基础。我们现在将在本研究计划中继续我们最近的新发现和假设。特别是，我们将解决有关DNA单链断裂修复在体内的组织和重要性的关键问题，重点关注XRCC 1的一种新的未识别的作用，以及这种蛋白质在单链断裂处被招募的机制，以及DNA单链断裂修复如何影响遗传性和衰老相关的退行性疾病。最终，我们设想这项工作将确定治疗和管理与DNA断裂完全或部分相关的退行性疾病的新途径。

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）

TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo.

DOI：
10.1371/journal.pgen.1003226
发表时间：
2013
期刊：
PLoS genetics
影响因子：
4.5
作者：
Gómez-Herreros F;Romero-Granados R;Zeng Z;Alvarez-Quilón A;Quintero C;Ju L;Umans L;Vermeire L;Huylebroeck D;Caldecott KW;Cortés-Ledesma F
通讯作者：
Cortés-Ledesma F

The Rev1 interacting region (RIR) motif in the scaffold protein XRCC1 mediates a low-affinity interaction with polynucleotide kinase/phosphatase (PNKP) during DNA single-strand break repair.

DOI：
10.1074/jbc.m117.806638
发表时间：
2017-09-29
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Breslin C;Mani RS;Fanta M;Hoch N;Weinfeld M;Caldecott KW
通讯作者：
Caldecott KW

The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function.

XRCC1磷酸盐结合口袋结合了聚（ADP-核糖），是XRCC1函数所必需的。

DOI：
10.1093/nar/gkv623
发表时间：
2015-08-18
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Breslin C;Hornyak P;Ridley A;Rulten SL;Hanzlikova H;Oliver AW;Caldecott KW
通讯作者：
Caldecott KW

Versatility in phospho-dependent molecular recognition of the XRCC1 and XRCC4 DNA-damage scaffolds by aprataxin-family FHA domains.

Aprataxin-Fha域对XRCC1和XRCC4 DNA破坏支架的磷酸依赖性分子识别的多功能性。

DOI：
10.1016/j.dnarep.2015.10.002
发表时间：
2015-11
期刊：
DNA repair
影响因子：
3.8
作者：
Cherry AL;Nott TJ;Kelly G;Rulten SL;Caldecott KW;Smerdon SJ
通讯作者：
Smerdon SJ

PARP3 is a sensor of nicked nucleosomes and monoribosylates histone H2B(Glu2).

DOI：
10.1038/ncomms12404
发表时间：
2016-08-17
期刊：
Nature communications
影响因子：
16.6
作者：
Grundy GJ;Polo LM;Zeng Z;Rulten SL;Hoch NC;Paomephan P;Xu Y;Sweet SM;Thorne AW;Oliver AW;Matthews SJ;Pearl LH;Caldecott KW
通讯作者：
Caldecott KW