Investigating the interplay between SMC complexes and Topoisomerase II

研究 SMC 复合物和拓扑异构酶 II 之间的相互作用

基本信息

  • 批准号:
    BB/S001425/1
  • 负责人:
  • 金额:
    $ 61.93万
  • 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

DNA is the repository for all the genetic information of a cell. To encode all this information DNA molecules are extraordinarily long. For example, a human cell contains nearly 2m of DNA in a nucleus smaller than 20 microns in diameter. Not only must all this DNA be packed into the nucleus but its organisation must be constantly re-organised so that its packaging can promote normal gene expression during most of the cell cycle before being tightly packaged during mitosis in a manner that allows faithful segregation of all chromosomes to daughter cells. Failure to appropriately organise chromosomes during the different stages of the cell cycle leads to chromosome fragility, aberrant chromosome numbers and cell death. Features often associated with cancer, ageing and human growth disorders.Two types of protein complexes appear to be essential to establish and maintain chromosomal organisation, SMC complexes and type II topoisomerases (Top2). The ancient family of SMC complexes are found in all the kingdoms of life, where they are required to appropriately structure chromosomes for genetic inheritance. Both the eukaryotic SMC complexes cohesin and condensin are thought to organise chromosomes by promoting DNA looping along chromosomes. Type II topoisomerases are also found in all cell types where they are thought to organize DNA by allowing one section of DNA to pass through another, promoting untangling of chromosomes and relaxing any DNA topological stress that builds up on the DNA. The eukaryotic type II topoisomerase Top2 is proposed to have both an enzymatic and structural role in chromosome structure. However, analysis to date of how SMC complexes and Top2 may work together to dynamically organise chromosome structure has produced seemingly contradictory results. Some of these studies indicate that SMC complexes and Top2 work in concert with each other to promote proper gene expression and chromosome segregation. However, others have found that they can also operate independently or even antagonistically in the maintenance of normal chromosome structure. These contrasting results indicate a complex and potentially context dependent interplay between Top2 and the different SMC complexes. Understanding the nature of this interplay is crucial for how these two ancient DNA manipulating machines work together to organise DNA and ensure normal biological function. Indeed, mutations in the genes encoding Top2 and SMC proteins are closely linked with cancer progression and the growth of animals and plants. In this proposal, we will investigate the interplay and co-dependencies of SMC complexes and Top2 on chromosome structure. Recently we have used the Hi-C chromosome conformation technique to show that cohesin and condensin organise the structure of budding yeast chromosomes in distinct ways. Here, we will examine how chromosome structure is altered by Top2 and how such changes are regulated by the different SMC complexes cohesin and condensin. We will go onto to examine if Top2 dependent changes to chromosome structure require the enzymatic activity of Top2 or only its binding to chromosomes and if these are regulated by SMC complexes. Finally, we will examine if DNA supercoiling and its regulation by Top2, and potentially SMCs, organizes chromosomes.Together this proposal aims to provide a comprehensive and coherent analysis of how the fundamental DNA structuring activities of Top2 and the SMC complexes cohesin and condensin interact to generate functional chromosome structure.
DNA是细胞所有遗传信息的储存库。为了编码所有这些信息,DNA分子非常长。例如,一个人类细胞在直径小于20微米的细胞核中含有近2 m的DNA。所有这些DNA不仅必须被包装到细胞核中,而且其组织必须不断重组,以便其包装可以在大部分细胞周期中促进正常基因表达,然后在有丝分裂期间以允许所有染色体忠实分离到子细胞的方式进行紧密包装。在细胞周期的不同阶段未能适当地组织染色体会导致染色体脆性、染色体数目异常和细胞死亡。通常与癌症、衰老和人类生长障碍相关的特征。两种类型的蛋白质复合物似乎对建立和维持染色体组织至关重要,SMC复合物和II型拓扑异构酶(Top2)。SMC复合物的古老家族存在于所有生命王国中,在那里它们被要求适当地构建染色体以进行遗传遗传。真核SMC复合物粘附素和凝聚素都被认为通过促进DNA沿染色体沿着成环来组织染色体。II型拓扑异构酶也存在于所有细胞类型中,它们被认为通过允许DNA的一个部分通过另一个部分来组织DNA,促进染色体的解开并放松在DNA上建立的任何DNA拓扑应力。真核II型拓扑异构酶Top2被提出在染色体结构中具有酶促和结构作用。然而,迄今为止,SMC复合物和Top2如何一起工作来动态组织染色体结构的分析产生了看似矛盾的结果。其中一些研究表明,SMC复合物和Top2相互协同工作,以促进适当的基因表达和染色体分离。然而,其他人发现它们也可以独立地或甚至拮抗地维持正常的染色体结构。这些对比结果表明Top2和不同SMC复合物之间存在复杂且可能依赖于背景的相互作用。了解这种相互作用的性质对于这两个古老的DNA操纵机器如何共同组织DNA并确保正常的生物功能至关重要。事实上,编码Top2和SMC蛋白的基因突变与癌症进展以及动植物的生长密切相关。在这个提议中,我们将研究SMC复合物和Top2对染色体结构的相互作用和相互依赖性。最近,我们已经使用Hi-C染色体构象技术表明,凝聚素和凝聚素以不同的方式组织芽殖酵母染色体的结构。在这里,我们将研究如何改变染色体结构的Top2和这种变化是如何调节不同的SMC复合物的凝聚素和凝聚素。我们将继续研究是否Top2依赖的染色体结构的变化需要Top2的酶活性或仅其与染色体的结合,以及这些是否受SMC复合物的调节。最后,我们将研究DNA超螺旋和它的调节Top2,并可能SMC,organizing chromosome.Together这一建议旨在提供一个全面的和连贯的分析如何基本的DNA结构活动的Top2和SMC复合物cohesin和condensin相互作用,以产生功能性染色体结构。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Checkpoint inhibition of origin firing prevents DNA topological stress.
原点激发的检查点抑制可防止 DNA 拓扑应力。
  • DOI:
    10.1101/gad.328682.119
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    10.5
  • 作者:
    Morafraile EC
  • 通讯作者:
    Morafraile EC
Principles of meiotic chromosome assembly revealed in S. cerevisiae
  • DOI:
    10.1038/s41467-019-12629-0
  • 发表时间:
    2019-10
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    S. Schalbetter;G. Fudenberg;J. Baxter;K. Pollard;Matthew J. Neale
  • 通讯作者:
    S. Schalbetter;G. Fudenberg;J. Baxter;K. Pollard;Matthew J. Neale
Telomerase subunit Est2 marks internal sites that are prone to accumulate DNA damage.
  • DOI:
    10.1186/s12915-021-01167-1
  • 发表时间:
    2021-11-20
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Pandey S;Hajikazemi M;Zacheja T;Schalbetter S;Neale MJ;Baxter J;Guryev V;Hofmann A;Heermann DW;Juranek SA;Paeschke K
  • 通讯作者:
    Paeschke K
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Jonathan Baxter其他文献

Author Correction to: Telomerase subunit Est2 marks internal sites that are prone to accumulate DNA damage
  • DOI:
    10.1186/s12915-022-01237-y
  • 发表时间:
    2022-02-01
  • 期刊:
  • 影响因子:
    4.500
  • 作者:
    Satyaprakash Pandey;Mona Hajikazemi;Theresa Zacheja;Stephanie Schalbetter;Matthew J. Neale;Jonathan Baxter;Victor Guryev;Andreas Hofmann;Dieter W. Heermann;Stefan A. Juranek;Katrin Paeschke
  • 通讯作者:
    Katrin Paeschke
Learning Internal Representations (PhD Thesis)
学习内部表征(博士论文)
  • DOI:
    10.1109/iecbes.2012.6498109
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jonathan Baxter
  • 通讯作者:
    Jonathan Baxter
The evolution of learning algorithms for artificial neural networks
  • DOI:
  • 发表时间:
    1993
  • 期刊:
  • 影响因子:
    1.2
  • 作者:
    Jonathan Baxter
  • 通讯作者:
    Jonathan Baxter
ArtLinks: fostering social awareness and reflection in museums
ArtLinks:培养博物馆的社会意识和反思
Using technologies to support reminiscence
使用技术来支持回忆
  • DOI:
    10.1145/1671011.1671073
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    0
  • 作者:
    D. Cosley;Kathy Akey;Brian Alson;Jonathan Baxter;M. Broomfield;Soyoung Lee;C. Sarabu
  • 通讯作者:
    C. Sarabu

Jonathan Baxter的其他文献

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{{ truncateString('Jonathan Baxter', 18)}}的其他基金

Determining how EBV episome maintenance is regulated by TIMELESS function
确定 TIMELESS 功能如何调节 EBV 附加体维持
  • 批准号:
    MR/X009432/1
  • 财政年份:
    2023
  • 资助金额:
    $ 61.93万
  • 项目类别:
    Research Grant
Investigating how replication fork rotation causes chromosomal instability during S phase
研究复制叉旋转如何导致 S 期染色体不稳定
  • 批准号:
    BB/N007344/1
  • 财政年份:
    2016
  • 资助金额:
    $ 61.93万
  • 项目类别:
    Research Grant
How does Condensin mediate topological change during mitosis?
Condensin 如何介导有丝分裂过程中的拓扑变化?
  • 批准号:
    BB/J018554/1
  • 财政年份:
    2012
  • 资助金额:
    $ 61.93万
  • 项目类别:
    Research Grant

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研究滑膜糖组在全身炎症和关节炎症之间相互作用中的作用。
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