Inter-Fork Strand Annealing: a novel mechanism that causes genomic deletions during the termination of DNA replication
叉间链退火:一种在 DNA 复制终止期间导致基因组缺失的新机制
基本信息
- 批准号:BB/P019706/1
- 负责人:
- 金额:$ 49.65万
- 依托单位:
- 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:
- 关键词:
项目摘要
Before a cell divides it has to replicate its genetic material so that each new daughter cell can receive a copy. This process of DNA replication occurs in the S-phase of the cell cycle and is performed by complex protein machines, which are assembled onto DNA at chromosomal sites known as replication origins. These machines unwind the DNA double helix to form "fork" structures, at which the copying occurs. During the S-phase, origins "fire" each releasing a pair of "replication forks" that travel in opposite directions away from their site of initiation. DNA replication is completed when forks from adjacent origins merge. Problems that occur during both the initiation and elongation phases of replication are well known to cause chromosomal alterations and catastrophic mutations that are instrumental in the ageing process, and in the development of age related diseases such as cancer. However, very little is known about the mutagenic potential of replication termination, when replication forks merge. Unlike replication initiation, replication termination can occur at any site in the genome and this makes it difficult to study. My laboratory has pioneered the use of site-specific replication fork barriers to focus termination at specific chromosomal locations. Using this approach we have discovered a novel process by which deletions of chromosomal DNA can occur during replication termination. The aim of this project is to determine exactly how these deletions arise, and the various factors that govern their occurrence. Deletions of chromosomal DNA erode the genetic information that is vital for maintaining the health and function of cells. By understanding the mechanisms that cause these deletions, and the factors that influence their frequency, we will be better placed in the future to assess an individual's capacity for healthy ageing, and to devise measures for assuaging the worst effects of the ageing process.
在细胞分裂之前,它必须复制它的遗传物质,以便每个新的子细胞都能获得一个副本。这种DNA复制过程发生在细胞周期的S阶段,由复杂的蛋白质机器执行,这些蛋白质机器在称为复制起点的染色体位置组装到DNA上。这些机器解开DNA双螺旋,形成“叉形”结构,复制发生在叉形结构上。在S阶段,起源“火”每个释放一对“复制叉子”向相反方向移动远离他们的起始点。当来自相邻来源的叉子合并时,DNA复制完成。众所周知,在复制的起始和延伸阶段发生的问题会导致染色体改变和灾难性突变,这对衰老过程和癌症等与年龄有关的疾病的发展是至关重要的。然而,对复制分叉合并时复制终止的突变潜力知之甚少。与复制启动不同,复制终止可以发生在基因组的任何位置,这使得研究变得困难。我的实验室率先使用了定点复制分叉屏障,将焦点终止在特定的染色体位置。使用这种方法,我们发现了一种新的过程,通过这种过程,染色体DNA可以在复制终止过程中发生删除。这个项目的目的是确切地确定这些缺失是如何产生的,以及控制它们发生的各种因素。染色体DNA的缺失会侵蚀对维持细胞健康和功能至关重要的遗传信息。通过了解导致这些缺失的机制和影响其频率的因素,我们将在未来更好地评估个人健康老龄化的能力,并制定措施减轻老龄化过程的最坏影响。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Rad52's DNA annealing activity drives template switching associated with restarted DNA replication.
- DOI:10.1038/s41467-022-35060-4
- 发表时间:2022-11-26
- 期刊:
- 影响因子:16.6
- 作者:Kishkevich, Anastasiya;Tamang, Sanjeeta;Nguyen, Michael O.;Oehler, Judith;Bulmaga, Elena;Andreadis, Christos;Morrow, Carl A.;Osman, Fekret;Whitby, Matthew C.
- 通讯作者:Whitby, Matthew C.
Gene duplication and deletion caused by over-replication at a fork barrier.
- DOI:10.1038/s41467-023-43494-7
- 发表时间:2023-11-25
- 期刊:
- 影响因子:16.6
- 作者:Oehler, Judith;Morrow, Carl A.;Whitby, Matthew C.
- 通讯作者:Whitby, Matthew C.
The PCNA unloader Elg1 promotes recombination at collapsed replication forks in fission yeast.
PCNA 卸载器 Elg1 促进裂殖酵母中折叠复制叉处的重组。
- DOI:10.7554/elife.47277
- 发表时间:2019
- 期刊:
- 影响因子:7.7
- 作者:Tamang S
- 通讯作者:Tamang S
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Matthew Whitby其他文献
Matthew Whitby的其他文献
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{{ truncateString('Matthew Whitby', 18)}}的其他基金
Investigating the factors that influence genome stability when replication forks encounter single-strand DNA breaks and protein roadblocks
研究复制叉遇到单链 DNA 断裂和蛋白质障碍时影响基因组稳定性的因素
- 批准号:
BB/V00073X/1 - 财政年份:2021
- 资助金额:
$ 49.65万 - 项目类别:
Research Grant
Elucidating the Rad51-independent pathway of recombination-dependent replication
阐明重组依赖性复制的独立于 Rad51 的途径
- 批准号:
MR/V009214/1 - 财政年份:2021
- 资助金额:
$ 49.65万 - 项目类别:
Research Grant
Elucidating the mechanisms that govern replication restart efficiency and fidelity
阐明控制复制重启效率和保真度的机制
- 批准号:
MR/P028292/1 - 财政年份:2018
- 资助金额:
$ 49.65万 - 项目类别:
Research Grant
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- 资助金额:21.0 万元
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