How does GG-NER complex-dependent chromatin remodeling initiate DNA damage recognition in chromatin by the Rad4-Rad23 damage recognition complex

GG-NER 复合物依赖性染色质重塑如何启动 Rad4-Rad23 损伤识别复合物对染色质中 DNA 损伤的识别

基本信息

  • 批准号:
    BB/R00756X/1
  • 负责人:
  • 金额:
    $ 40.1万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2018
  • 资助国家:
    英国
  • 起止时间:
    2018 至 无数据
  • 项目状态:
    已结题

项目摘要

All forms of life contain within their cells the encrypted information necessary for coordinating the function of individual cells and the organism as a whole. The information is stored in the nucleus of the cell within a large molecule called deoxyribonucleic acid [DNA], sometimes referred to as the double helix. This information is divided into units called genes, and the sum of all the genetic material of an organism is referred to as its genome. DNA might be expected to be extremely stable and resistant to change, since altering the coded message could cause genes to malfunction. 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 acquired differences in the genetic material of each individual - a process is known as evolution. Much of the genetic variation within the human population is the result of 'reshuffling' the genes during sexual reproduction - this is called recombination. However, changes in the genetic material can occur by other means. DNA can be damaged by the normal events occuring within the cell, as well as physical or chemical damage from the environment, including ultraviolet radiation from sunlight. Each of our cells receives thousands of DNA lesions each day. The vast majority of this damage, if left unchecked, would result in the rapid loss of the information contained in the genetic material, since replication of damaged DNA during normal cell division can permanently alter the genetic code. These heritable changes are called mutations. During evolution mechanisms that can repair DNA have been encoded in the genome of all organisms and these are fundamental to maintaining the stability of the genome. People with defects in the genes controlling these DNA repair pathways suffer serious diseases, but it is now understood that collectively these repair mechanisms are fundamental to normal DNA function.Our research aims to understand how one of these processes, nucleotide excision repair [NER] operates. Much of our knowledge has come from the study of NER in a variety of different organisms including yeast. The process is remarkably similar in yeast and human cells, and studying NER in yeast continues to inform on the mechanism of this process. DNA repair is integrated with other cellular process including the ubiquitin proteasome pathway [UPP]. Our laboratory has made important discoveries into how these pathways interact, uncovering a new E3 ubiquitin ligase, a part of the UPP, which connects the activity of the proteasome to NER. This ubiquitin ligase controls how cells respond to DNA damage. We recently uncovered an unanticipated regulatory mechanism that integrates the ubiquitination of DNA repair factors with the regulation of gene transcription. We showed that DNA damage recognition factors involved in NER, can also bind to the promoters of certain genes in the absence of damage. In this context, the repair factors can switch off gene transcription. In response to DNA damage, and in a manner dependent on ubiquitination of Rad4, the damage recognition factors are released from these promoters and this allows the damage-induced transcription of these genes. In this application, we plan to investigate how the GG-NER chromatin remodelling complex regulates the activity of the DNA damage recognition complex, promoting efficient recognition of UV induced lesions in chromatin. Understanding how DNA damage is recognised in chromatin is of central importance, because recently it has been reported that many novel cancer causing genes that have been identified from cancer genome sequencing projects turn out to be involved in the chromatin remodelling process. It is likely that defective chromatin remodelling will cause genomic instability, possibly in specific regions of the genome, giving rise to tumourigenesis. This project seeks to understand how UV damage recognition occurs throughout the genome.
所有形式的生命都在其细胞内包含协调单个细胞和整个有机体功能所必需的加密信息。这些信息储存在细胞核中的一个叫做脱氧核糖核酸(DNA)的大分子中,有时也被称为双螺旋。这些信息被分成称为基因的单位,生物体所有遗传物质的总和被称为基因组。DNA可能被认为是非常稳定和抗改变的,因为改变编码信息可能会导致基因故障。另一方面,生物体能够通过群体内的遗传变异来适应环境的变化,这种遗传变异是由每个个体遗传物质的后天差异引起的,这一过程被称为进化。人类群体中的大部分遗传变异是有性生殖过程中基因“重组”的结果-这被称为重组。然而,遗传物质的变化可以通过其他方式发生。DNA可以被细胞内发生的正常事件以及来自环境的物理或化学损伤所破坏,包括来自阳光的紫外线辐射。我们的每个细胞每天都会受到成千上万的DNA损伤。如果不加以控制,绝大多数这种损伤将导致遗传物质中包含的信息迅速丢失,因为在正常细胞分裂期间受损DNA的复制可以永久改变遗传密码。这些可遗传的变化被称为突变。在进化过程中,可以修复DNA的机制已经编码在所有生物体的基因组中,这些机制对于维持基因组的稳定性至关重要。控制这些DNA修复途径的基因有缺陷的人会患上严重的疾病,但现在人们知道,这些修复机制对正常的DNA功能至关重要。我们的研究旨在了解其中一个过程,核苷酸切除修复[NER]是如何运作的。我们的大部分知识来自于对包括酵母在内的各种不同生物体中NER的研究。这一过程在酵母和人类细胞中非常相似,研究酵母中的NER将继续为这一过程的机制提供信息。DNA修复与其他细胞过程整合,包括泛素蛋白酶体途径[UPP]。我们的实验室在这些途径如何相互作用方面取得了重要发现,发现了一种新的E3泛素连接酶,它是UPP的一部分,将蛋白酶体的活性与NER联系起来。这种泛素连接酶控制细胞如何对DNA损伤做出反应。我们最近发现了一个意想不到的调控机制,整合了DNA修复因子的泛素化与基因转录的调控。我们发现,参与NER的DNA损伤识别因子也可以在没有损伤的情况下与某些基因的启动子结合。在这种情况下,修复因子可以关闭基因转录。响应于DNA损伤,并且以依赖于Rad 4的泛素化的方式,损伤识别因子从这些启动子释放,这允许这些基因的损伤诱导的转录。在本申请中,我们计划研究GG-NER染色质重塑复合物如何调节DNA损伤识别复合物的活性,促进染色质中UV诱导的损伤的有效识别。了解DNA损伤如何在染色质中被识别是至关重要的,因为最近有报道称,许多从癌症基因组测序项目中鉴定出的新的致癌基因参与了染色质重塑过程。有缺陷的染色质重塑可能会导致基因组的不稳定性,可能在基因组的特定区域,引起肿瘤发生。该项目旨在了解紫外线损伤识别如何在整个基因组中发生。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Precision digital mapping of endogenous and induced genomic DNA breaks by INDUCE-seq.
  • DOI:
    10.1038/s41467-022-31702-9
  • 发表时间:
    2022-07-09
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
  • 通讯作者:
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。
  • DOI:
    10.1101/gr.237198.118
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    7
  • 作者:
    Van Eijk P
  • 通讯作者:
    Van Eijk P
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Simon Reed其他文献

Specification and Quantitative Analysis of Probabilistic Cloud Deployment Patterns
概率云部署模式的规范和定量分析
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kenneth Johnson;Simon Reed;R. Calinescu
  • 通讯作者:
    R. Calinescu

Simon Reed的其他文献

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{{ truncateString('Simon Reed', 18)}}的其他基金

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
  • 批准号:
    MR/K000926/1
  • 财政年份:
    2013
  • 资助金额:
    $ 40.1万
  • 项目类别:
    Research Grant

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衍射光学三维信息加密与隐藏的研究
  • 批准号:
    60907004
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    2009
  • 资助金额:
    22.0 万元
  • 项目类别:
    青年科学基金项目

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