Integrating chromatin structure and global chromosome dynamics

整合染色质结构和整体染色体动力学

• 批准号: BB/F02391X/1
• 负责人: Eugenio Sanchez-Moran
• 金额: $ 96.3万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF02391X%2F1
• 关键词: Integrating; chromatin; structure; global; chromosome

The role of DNA is to store an individual's genetic information such that it can be used during normal growth and development and be accurately copied during the different divisions of the cell. Human cells contain DNA totalling about 2 m in length that has to be packed within the cell nucleus which is only 0.01 mm in diameter. Importantly, the DNA must be organised in such a way that it is readily accessible for a variety of crucial processes. The information it contains must be easily read (transcription) so that the cell can rapidly produce proteins. It must be readily duplicated (DNA replication) and accurately separated during cell division (mitosis) and sexual reproduction (meiosis). Also, it is essential that any break, knot or tangle that might occur can be repaired (DNA repair). DNA associates with different proteins forming a nucleo-protein complex called chromatin. This enables the compaction necessary to fit the naked DNA inside the cell nucleus whilst maintaining access to the genetic information. The chromatin is divided into individual structures constituting chromosomes. During the process of cell division when the individual chromosomes have been duplicated chromosome condensation is necessary to ensure their accurate distribution. Miss-regulation of chromosome condensation can lead to cell death, cancer and improper chromosome segregation during cell cycle or during the production of gametes. There are different levels of compaction involved in packaging DNA into chromosomes. The basic structure is the nucleosome, formed by wrapping naked DNA around a core of proteins known as histones. The nucleosomes are arranged along the DNA forming a 10nm diameter fibre, likened to beads on a string. Despite the old impression that nucleosomes were static structures, nowadays, a nucleosome is considered as a highly dynamic assemblage. Changes to this organised structure are facilitated through histone modifications, modelling factors and exchange of histone proteins. The nucleosomal fibre is further compacted by winding it into a 30 nm fibre whose structure remains controversial. This fibre is additionally arranged into loops that are attached to a multi-protein axis called the chromosome scaffold. Although the biochemistry of histones and other chromosome-associated proteins has been studied intensively, their interactions to achieve chromosome condensation are still poorly understood. My research project aims to unravel the biological significance that the different levels of DNA compaction structures and components have on chromosome condensation in the nucleus. The correct chromosome condensation is essential for the stability of the genetic information. This project will contribute to the understanding of different important and interesting subjects like cell division, cancer, stem cells, chromosome alterations, fertility and plant breeding. The key proteins involved in chromosome condensation are conserved throughout eukaryotic evolution indicating that they are likely to have fundamental roles that are species-independent. I will be using Arabidopsis thaliana, a plant model organism for basic research in genetics and molecular biology and a good experimental system without any of the ethical issues related to working with animals. Furthermore, I have developed a range of molecular cytogenetic techniques that have contributed to the study of chromosome dynamics in Arabidopsis. I have recently found exciting evidence that some histone and chromosome scaffold mutants are affected in chromosome condensation at different levels. Thus, I would like to conduct a thorough analysis of these and other related proteins. I propose to use a multidisciplinary approach combining new high-resolution cytogenetic techniques, mutant characterisation, proteomic analysis, and mathematical models to resolve the complicated interactions of individual chromatin components that result in accurate chromosome condensation.

DNA的作用是储存个体的遗传信息，以便在正常生长和发育期间使用，并在细胞的不同分裂期间准确复制。人类细胞含有总长度约为2 m的DNA，其必须被包装在直径仅为0.01 mm的细胞核内。重要的是，DNA的组织方式必须使其易于用于各种关键过程。它所包含的信息必须很容易阅读（转录），以便细胞能够快速产生蛋白质。它必须容易复制（DNA复制），并在细胞分裂（有丝分裂）和有性生殖（减数分裂）过程中准确分离。此外，重要的是，任何可能发生的断裂，结或缠结都可以修复（DNA修复）。DNA与不同的蛋白质结合，形成称为染色质的核蛋白复合物。这使得在保持对遗传信息的访问的同时，使裸DNA在细胞核内适合所需的压缩成为可能。染色质被分成构成染色体的单个结构。在细胞分裂过程中，当单个染色体复制完成时，染色体浓缩是必要的，以确保它们的准确分布。染色体凝聚的错误调节可导致细胞死亡、癌症和细胞周期或配子产生期间的染色体分离不当。在将DNA包装成染色体的过程中涉及不同水平的压实。其基本结构是核小体，由裸露的DNA包裹在被称为组蛋白的蛋白质核心周围形成。核小体沿着DNA排列，形成直径10纳米的纤维，就像一根绳子上的珠子。尽管核小体是静态结构的旧印象，如今，核小体被认为是一个高度动态的组合。这种有组织的结构的变化是通过组蛋白修饰，建模因子和组蛋白蛋白的交换来促进的。核小体纤维通过将其缠绕成30 nm纤维而进一步压缩，其结构仍有争议。这种纤维还被排列成环，连接到称为染色体支架的多蛋白质轴上。虽然组蛋白和其他染色体相关蛋白的生物化学已被深入研究，它们之间的相互作用，以实现染色体凝聚仍然知之甚少。我的研究项目旨在揭示不同水平的DNA压缩结构和组分对细胞核中染色体浓缩的生物学意义。正确的染色体浓缩对遗传信息的稳定性至关重要。该项目将有助于了解不同的重要和有趣的主题，如细胞分裂，癌症，干细胞，染色体改变，生育和植物育种。参与染色体凝聚的关键蛋白在整个真核生物进化过程中是保守的，这表明它们可能具有不依赖于物种的基本作用。我将使用拟南芥，一种用于遗传学和分子生物学基础研究的植物模式生物，以及一个良好的实验系统，没有任何与动物相关的伦理问题。此外，我还开发了一系列分子细胞遗传学技术，有助于拟南芥染色体动力学的研究。我最近发现了令人兴奋的证据，一些组蛋白和染色体支架突变体在不同水平上影响染色体浓缩。因此，我想对这些和其他相关蛋白质进行彻底的分析。我建议使用一个多学科的方法相结合的新的高分辨率细胞遗传学技术，突变体特征，蛋白质组学分析，和数学模型，以解决复杂的相互作用的个别染色质成分，导致准确的染色体浓缩。

项目成果

Location and dynamics of an active promoter in Escherichia coli K-12.

• DOI: 10.1042/bj20111258
• 发表时间: 2012-01-01
• 期刊: The Biochemical journal
• 作者: Sánchez-Romero MA;Lee DJ;Sánchez-Morán E;Busby SJ
• 通讯作者: Busby SJ

The Role of Topoisomerase II in DNA Repair and Recombination in Arabidopsis thaliana.

• DOI: 10.3390/ijms222313115
• 发表时间: 2021-12-04
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Martinez-Garcia M;White CI;Franklin FCH;Sanchez-Moran E
• 通讯作者: Sanchez-Moran E

The Role of DNA Topoisomerase Binding Protein 1 (TopBP1) in Genome Stability in Arabidopsis.

DNA拓扑异构酶结合蛋白1（TOPBP1）在拟南芥中基因组稳定性中的作用。

• DOI: 10.3390/plants10122568
• 发表时间: 2021-11-24
• 期刊: Plants (Basel, Switzerland)
• 作者: Parra-Nunez P;Cooper C;Sanchez-Moran E
• 通讯作者: Sanchez-Moran E

TOPII and chromosome movement help remove interlocks between entangled chromosomes during meiosis.

• DOI: 10.1083/jcb.201803019
• 发表时间: 2018-12-03
• 期刊: The Journal of cell biology
• 作者: Martinez-Garcia M;Schubert V;Osman K;Darbyshire A;Sanchez-Moran E;Franklin FCH
• 通讯作者: Franklin FCH

Together yes, but not coupled: new insights into the roles of RAD51 and DMC1 in plant meiotic recombination.

• DOI: 10.1111/j.1365-313x.2011.04845.x
• 发表时间: 2012-03
• 期刊: The Plant journal : for cell and molecular biology
• 作者: M. Pradillo;E. López;R. Linacero;C. Romero;N. Cuñado;E. Sanchez-Moran;J. Santos