Unravelling the role of topoisomerase II beta binding protein 1 (TOPBP1) in the resolution of ultra-fine anaphase bridges.
揭示拓扑异构酶 II β 结合蛋白 1 (TOPBP1) 在解析超细后期桥中的作用。
基本信息
- 批准号:BB/T009608/1
- 负责人:
- 金额:$ 38.83万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Fellowship
- 财政年份:2020
- 资助国家:英国
- 起止时间:2020 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
During every cell division, the genetic code must be accurately copied and separated between two daughter cells. Faithful division of the genome is vital to prevent damage during cell division. The processes which govern this process are conserved throughout evolution. Furthermore, there is a greater imperative for the accuracy of these processes in complex multicellular organisms, such as humans, who rely on the cooperation between functional organs and tissues. Errors in these mechanisms in the early stages of development may lead to dysfunction or prove lethal to the organism. Despite this, our current understanding of the fundamental processes that the class of proteins known as topoisomerases engage in to untangle and separate the duplicated genome remains poor. Cells that cannot resolve entangled DNA develop 'chromatin bridges' and these bridges may lead to the loss or rearrangement of genomic information leading to changes in the number or structure of chromosomes (chromosomal instability). These bridges can be divided into two distinct classes based on their ability to be stained with conventional DNA dyes i.e. stainable "anaphase bridges" or non-stainable "ultrafine anaphase bridges" (UFBs). Subsequently dysfunction in the processes of chromosomal separation pose a challenge to human health through development of cancer or as a feature of genetic diseases which demonstrate lifelong morbidity. In accordance, genes that regulate these mechanisms are potent tumour suppressors, whereas drugs that target them, are amongst the most successful anti-cancer modalities. Taken together, there is an indication that the evolutionarily conserved mechanisms of chromosomal segregation are fundamental in nature and essential to the normal function of every cell. To provide insight into these mechanisms the aim of this project is to explore the role of the protein DNA topoisomerase II binding protein 1 (TOPBP1) in recruiting the DNA topoisomerase II alpha (TOP2A) to UFBs leading to their resolution during cell division. To achieve this, three research objectives will be addressed with the aid of a collaborative network of scientists. I). To identify the mechanisms of recruitment of TOPBP1 to UFBs; Collaboration with the Functional Proteomics group, will aid in the identification of TOPBP1 interacting proteins and the modifications which signal their localisation at UFBs. Downregulation of identified protein interactors will be employed collaboration with the Gene Function Team at the ICR, to determine their impact on TOP2A/TOPBP1 recruitment to UFBs and viability of cells. II). To characterise the molecular basis of the TOPBP1-TOP2A interaction; collaboration with the Division of Structural Biology at the ICR, will assist in the purification of TOPBP1 and TOP2A proteins from bacteria and/or insect cells. This will enable the identification of the interacting surfaces of TOP2A and TOPBP1 and study of the structure of the complex that they may form. III). To determine how this interaction promotes TOP2A recruitment to UFBs and aids their resolution; The light microscopy facilities at the ICR will be used to analyse normal and dysfunctional cells that express key TOP2A and TOPBP1 mutant proteins, to determine their ability to be recruited to UFBs and resolve them.The findings of the proposed project will further our understanding of the fundamental TOP2A-TOPBP1 processes that regulate faithful division of the genome during cell division, providing insight into how dysfunction in these processes impacts on human health, leading to pathologies such as cancer.During this project a collaborative scientific network will be established which will aid in the acquisition of experience in a broad spectrum of experimental techniques. This will be essential for my professional development towards becoming a principal investigator who will investigate the molecular mechanisms that underpin faithful chromosomal segregation during mitosis.
在每一次细胞分裂过程中,必须在两个子细胞之间准确复制和分离遗传密码。基因组的忠实分裂对于防止细胞分裂过程中的损害至关重要。支配这一过程的过程在整个进化过程中都是保守的。此外,在复杂的多细胞生物体中,例如依赖于功能器官和组织之间的合作的人类,对这些过程的准确性有更大的必要性。在发育的早期阶段,这些机制中的错误可能会导致功能障碍,或者被证明对生物体是致命的。尽管如此,我们目前对被称为拓扑异构酶的一类蛋白质参与解开和分离复制基因组的基本过程的了解仍然很差。不能分解缠结的DNA的细胞会形成“染色质桥”,这些桥可能会导致基因组信息的丢失或重新排列,从而导致染色体数量或结构的变化(染色体不稳定)。根据它们能被常规DNA染料染色的能力,这些桥可以分为两类,即可染色的“后期桥”或不可染色的“超细后期桥”(UFBs)。因此,染色体分离过程中的功能障碍对人类健康构成了挑战,因为它会发展成癌症,或作为遗传病的一个特征,表现出终生的发病率。因此,调节这些机制的基因是有效的肿瘤抑制因子,而针对它们的药物是最成功的抗癌方式之一。综上所述,有一个迹象表明,进化上保守的染色体分离机制在本质上是基本的,对每个细胞的正常功能都是必不可少的。为了深入了解这些机制,本项目的目的是探索蛋白质DNA拓扑异构酶II结合蛋白1(TOPBP1)在将DNA拓扑异构酶IIα(TOP2A)招募到UFBs中的作用,从而导致它们在细胞分裂过程中的分解。为了实现这一目标,将在科学家合作网络的帮助下解决三个研究目标。i)。识别TOPBP1向UFBs募集的机制;与功能蛋白质组学小组合作,将有助于识别TOPBP1相互作用的蛋白质及其在UFBs定位的修饰。将与ICR的基因功能团队合作,下调已确定的蛋白质相互作用因子,以确定它们对TOP2A/TOPBP1向UFBs的募集和细胞活力的影响。Ii)。描述TOPBP1-TOP2A相互作用的分子基础;与ICR结构生物学司合作,将有助于从细菌和/或昆虫细胞中纯化TOPBP1和TOP2A蛋白质。这将使识别TOP2A和TOPBP1的相互作用表面并研究它们可能形成的络合物的结构成为可能。三)。为了确定这种相互作用如何促进TOP2A招募到UFBs并帮助它们分解;ICR的光学显微镜设施将被用来分析表达关键TOP2A和TOPBP1突变蛋白的正常和功能失调的细胞,以确定它们被招募到UFBs并解决它们的能力。拟议项目的发现将进一步加深我们对基本TOP2A-TOPBP1过程的理解,该过程调节细胞分裂过程中基因组的忠实分裂,洞察这些过程中的功能障碍如何影响人类健康,导致癌症等病理。在这个项目期间,将建立一个协作的科学网络,这将有助于在广泛的实验技术中获得经验。这对于我的职业发展是至关重要的,我将成为一名首席研究员,研究在有丝分裂过程中支撑忠实染色体分离的分子机制。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Actin nucleation safeguards single-stranded DNA and promotes replication fork protection
肌动蛋白成核可保护单链 DNA 并促进复制叉保护
- DOI:10.21203/rs.3.rs-806457/v1
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Nieminuszczy J
- 通讯作者:Nieminuszczy J
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Peter Martin其他文献
Ion Implantation: Tribological Applications
- DOI:
10.1002/9781119308713.ch13 - 发表时间:
2016-08 - 期刊:
- 影响因子:0
- 作者:
Peter Martin - 通讯作者:
Peter Martin
Guidelines for managing people with diabetes at the end of life : Final report 2010
糖尿病患者临终管理指南:2010 年最终报告
- DOI:
- 发表时间:
2010 - 期刊:
- 影响因子:0
- 作者:
T. Dunning;Peter Martin;S. Savage;N. Duggan - 通讯作者:
N. Duggan
A Pipelined Hardware Implementation of Genetic Programming Using FPGAs and Handel-C
使用 FPGA 和 Handel-C 的流水线硬件实现遗传编程
- DOI:
10.1007/3-540-45984-7_1 - 发表时间:
2002 - 期刊:
- 影响因子:0
- 作者:
Peter Martin - 通讯作者:
Peter Martin
Crossover Operators For A Hardware Implementation Of GP Using FPGAs And Handel-C
使用 FPGA 和 Handel-C 进行 GP 硬件实现的交叉算子
- DOI:
- 发表时间:
2002 - 期刊:
- 影响因子:0
- 作者:
Peter Martin;R. Poli - 通讯作者:
R. Poli
Real-time Neuro-fuzzy Trajectory Generation for Robotic Rehabilitation Therapy
用于机器人康复治疗的实时神经模糊轨迹生成
- DOI:
- 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
Peter Martin;M. Emami - 通讯作者:
M. Emami
Peter Martin的其他文献
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{{ truncateString('Peter Martin', 18)}}的其他基金
Ultimate Liquids' Technology for Responsive, Agile & FLEXible MANUfac
Ultimate Liquids 的响应灵敏、敏捷的技术
- 批准号:
EP/K503666/1 - 财政年份:2013
- 资助金额:
$ 38.83万 - 项目类别:
Research Grant
Biosurfactant process engineering and a new era of white unit operations
生物表面活性剂工艺工程和白色单元操作的新时代
- 批准号:
EP/I024905/1 - 财政年份:2011
- 资助金额:
$ 38.83万 - 项目类别:
Research Grant
A Novel Process for the Continuous Production of Surfactin
连续生产表面活性素的新工艺
- 批准号:
EP/D073227/2 - 财政年份:2007
- 资助金额:
$ 38.83万 - 项目类别:
Research Grant
A Novel Process for the Continuous Production of Surfactin
连续生产表面活性素的新工艺
- 批准号:
EP/D073227/1 - 财政年份:2006
- 资助金额:
$ 38.83万 - 项目类别:
Research Grant
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