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Determining how global genome nucleotide excision repair promotes efficient removal of DNA damage from chromatin

确定全局基因组核苷酸切除修复如何促进有效去除染色质中的 DNA 损伤

基本信息

批准号：
MR/K000926/1
负责人：
Simon Reed
金额：
$ 44.14万
依托单位：
CARDIFF UNIVERSITY
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK000926%2F1
关键词：
Determining how global genome nucleotide

项目摘要

Contained within each of our cells is the coded information necessary for life. The information is stored in a compartment of the cell called the nucleus which contains a large molecule with a remarkable structure called deoxyribonucleic acid - DNA. The information within the DNA is divided into units called chromosomes which are further subdivided into genes. DNA is packaged into chromatin in order to compact the genetic material in the nucleus and the sum of all the genetic material of an organism is referred to as its genome. It might be anticipated that life's coded information would be extremely stable and resistant to change, since errors in the code could have serious consequences. On the other hand, organisms are able to adapt to changes in their environment by virtue of the genetic variation within the population caused by alterations in the genetic material of individuals. This process is known as evolution. In the human population a lot of genetic variation is the result of 'reshuffling' of the genes during sexual reproduction. However, DNA can also be altered by normal processes operating within the cell, as well as physical or chemical damage from the environment, including ultraviolet radiation from sunlight. The DNA in each of our cells is continuously damaged by such agents. If left unchecked this would quickly erode the genetic information, since copying damaged DNA when cells divide can permanently alter the genetic code - a process called mutation. Over time, a variety of different DNA repair pathways have evolved which serve to prevent this from occuring. Collectively these are fundamental to the stability of the genome. People who inherit defects in the genes controlling these DNA repair pathways are more likely to suffer from certain cancers and other diseases. Our research aims to understand how one of these processes, nucleotide excision repair [NER] operates. People with defects in genes regulating this process suffer highly elevated levels of skin and other cancers. Molecular studies have revealed how defects in different genes involved in the process can result in a number of clinically distinct diseases. Much of our knowledge has come from the study of NER in a variety of different organisms. We study NER in bakers' yeast. Amazingly, the mechanism in yeast is remarkably similar to that in human cells, underlining the fundamental significance of this process. The work described in this proposal aims to help us understand how the NER process is organised in the genome and how lesions are removed from chromatin following UV induced DNA damage. It is emerging that the sensors of DNA damage in chromatin are playing an important role in how DNA repair is regulated in the cell. Research into DNA repair has entered a new phase of discovery, revealing how the various DNA repair mechanisms are controlled in response to DNA damage and how the pathways are integrated with one another. In addition to improving our understanding of the molecular basis of human disease syndromes, novel synthetic genetic interactions between the pathways are identifying new targets for novel and improved cancer treatments. At present our knowledge of how the NER pathway operates in chromatin and how this process is regulated lags behind our knowledge in other repair pathways. The work carried out in this proposal will significantly improve our knowledge in this area providing significant insight for further human studies.

我们每个细胞内都包含着生命所必需的编码信息。这些信息储存在细胞的一个叫做细胞核的隔间里，细胞核里有一个叫做脱氧核糖核酸的大分子。DNA中的信息被分成称为染色体的单位，染色体又被进一步细分为基因。DNA被包装到染色质中，以便将遗传物质压缩在细胞核中，生物体所有遗传物质的总和被称为其基因组。可以预见，生命的编码信息将非常稳定，并且不会改变，因为代码中的错误可能会产生严重的后果。另一方面，生物体能够通过个体遗传物质的改变引起的种群内遗传变异来适应环境的变化。这个过程被称为进化。在人类群体中，许多遗传变异是有性生殖过程中基因“重新洗牌”的结果。然而，DNA也可以被细胞内的正常过程改变，以及来自环境的物理或化学损伤，包括来自阳光的紫外线辐射。我们每个细胞中的DNA都被这些物质持续破坏。如果不加以控制，这将迅速侵蚀遗传信息，因为当细胞分裂时复制受损的DNA可以永久改变遗传密码-这一过程称为突变。随着时间的推移，各种不同的DNA修复途径已经进化出来，有助于防止这种情况的发生。总的来说，这些对基因组的稳定性至关重要。控制这些DNA修复途径的基因中遗传缺陷的人更有可能患有某些癌症和其他疾病。我们的研究旨在了解其中一个过程，核苷酸切除修复[NER]如何运作。调节这一过程的基因有缺陷的人患皮肤癌和其他癌症的水平非常高。分子研究揭示了参与该过程的不同基因的缺陷如何导致许多临床上不同的疾病。我们的大部分知识来自于对各种不同生物体中NER的研究。我们研究了面包酵母中的NER。令人惊讶的是，酵母中的机制与人类细胞中的机制非常相似，强调了这一过程的根本意义。本提案中描述的工作旨在帮助我们了解NER过程在基因组中是如何组织的，以及UV诱导的DNA损伤后如何从染色质中去除病变。染色质中的DNA损伤传感器在细胞中DNA修复的调节中起着重要作用。对DNA修复的研究已经进入了一个新的发现阶段，揭示了各种DNA修复机制如何响应DNA损伤以及这些途径如何相互整合。除了提高我们对人类疾病综合征的分子基础的理解外，这些途径之间的新型合成遗传相互作用正在为新型和改进的癌症治疗确定新的靶点。目前，我们对NER途径在染色质中如何运作以及该过程如何调节的知识落后于我们对其他修复途径的知识。在这项提案中进行的工作将大大提高我们在这一领域的知识，为进一步的人类研究提供重要的见解。

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）

Human basal cell carcinoma tumor-initiating cells are resistant to etoposide.

人基底细胞癌肿瘤起始细胞对依托泊苷具有耐药性。

DOI：
10.1038/jid.2013.377
发表时间：
2014
期刊：
The Journal of investigative dermatology
影响因子：
0
作者：
Colmont CS
通讯作者：
Colmont CS

Global genome nucleotide excision repair is organized into domains that promote efficient DNA repair in chromatin.

DOI：
10.1101/gr.209106.116
发表时间：
2016-10
期刊：
Genome research
影响因子：
7
作者：
Yu S;Evans K;van Eijk P;Bennett M;Webster RM;Leadbitter M;Teng Y;Waters R;Jackson SP;Reed SH
通讯作者：
Reed SH

Nucleosome remodeling at origins of global genome-nucleotide excision repair occurs at the boundaries of higher-order chromatin structure.

全球基因组核苷酸切除修复起源的核小体重塑发生在高级染色质结构的边界处。