How does Structural Maintenance of Chromosomes (SMC) protein interact with DNA to organise bacterial chromosomes?

染色体结构维护 (SMC) 蛋白如何与 DNA 相互作用来组织细菌染色体？

• 批准号: BB/P018165/1
• 负责人: Tung Le
• 金额: $ 50.44万
• 依托单位: John Innes Centre
• 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: https://gtr.ukri.org/projects?ref=BB%2FP018165%2F1
• 关键词: How; does; Structural; Maintenance; Chromosomes

DNA, the genetic blueprint of living organisms, uses a 4-letter code to define the instructions for organisms to grow and replicate. As the encoded information is very large, the DNA string is extremely long. To fit this string into the restricted space of the cell, the DNA must be folded in a specific way in 3-dimensional space. This folding has extremely important implications for the functioning of all living organisms and yet it is very poorly understood how this structure is established and maintained, especially in bacteria. This research proposal aims to understand how a protein called Structural Maintenance of Chromosomes (SMC) folds the chromosome in an aquatic bacterium called Caulobacter crescentus. Specifically, we aim to:(i) understand the behaviour of individual SMC molecule in the cell when they are on or off DNA(ii) understand how RNA polymerases move SMC around on the chromosome(iii) discover new interacting partners that together with SMC organise the bacterial chromosomeThe Caulobacter SMC protein is similar to human proteins called condensin and cohesin. Defective cohesin or condensin contributes to tumour formation. Indeed, in colorectal cancer, a significant fraction of cancerous tissues was found to have defects in cohesin or associated genes. In addition, defective cohesin was thought to cause the genetic disease Cornelia deLange syndrome. The affected children have defects such as missing fingers, mental retardation, growth failure, heart defects, and other impairments. I anticipate that, by employing a simpler living organism, my research into the role of SMC in Caulobacter will reveal an ancient, core function of the SMC family of proteins and thereby provide insights into the functions of human cohesin and condensin and how their malfunctions result in disease.

DNA是生物体的遗传蓝图，它使用4个字母的代码来定义生物体生长和复制的指令。由于编码的信息非常大，DNA串非常长。为了将这条线放入细胞的有限空间，DNA必须在三维空间中以特定的方式折叠。这种折叠对所有生物体的功能具有极其重要的意义，但人们对这种结构是如何建立和维持的知之甚少，特别是在细菌中。这项研究计划旨在了解一种名为染色体结构维持（SMC）的蛋白质如何在一种名为Caulobacter crescentus的水生细菌中折叠染色体。具体来说，我们的目标是：（i）了解单个SMC分子在细胞中的行为，当它们在DNA上或不在DNA上时（ii）了解RNA聚合酶如何在染色体上移动SMC（iii）发现新的相互作用伙伴，与SMC一起组织细菌染色体。有缺陷的粘附素或凝聚素有助于肿瘤形成。事实上，在结直肠癌中，发现相当大一部分癌组织具有粘附素或相关基因的缺陷。此外，有缺陷的黏连蛋白被认为是导致遗传疾病科尔内利亚德兰格综合征的原因。受影响的儿童有缺陷，如手指缺失，智力迟钝，生长障碍，心脏缺陷和其他损伤。我预计，通过采用更简单的生物体，我对SMC在柄杆菌中的作用的研究将揭示SMC蛋白质家族的古老核心功能，从而深入了解人类粘附素和凝聚素的功能以及它们的故障如何导致疾病。

项目成果

Chromosome Conformation Capture with Deep Sequencing to Study the Roles of the Structural Maintenance of Chromosomes Complex In Vivo.

通过深度测序捕获染色体构象，研究体内染色体复合体结构维持的作用。

• DOI: 10.1007/978-1-4939-9520-2_9
• 发表时间: 2019
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Le TBK

CTP regulates membrane-binding activity of the nucleoid occlusion protein Noc

CTP 调节类核封闭蛋白 Noc 的膜结合活性

• DOI: 10.1101/2021.02.11.430593
• 发表时间: 2021
• 作者: Jalal A

A CTP-dependent gating mechanism enables ParB spreading on DNA.

• DOI: 10.7554/elife.69676
• 发表时间: 2021-08-16
• 期刊: eLife
• 影响因子: 7.7
• 作者: Jalal AS;Tran NT;Stevenson CE;Chimthanawala A;Badrinarayanan A;Lawson DM;Le TB
• 通讯作者: Le TB

Diversification of DNA-binding specificity via permissive and specificity-switching mutations in the ParB/Noc protein family

通过 ParB/Noc 蛋白家族的允许突变和特异性转换突变实现 DNA 结合特异性的多样化

• DOI: 10.1101/724823
• 发表时间: 2019
• 作者: Jalal A

ParB spreading on DNA requires cytidine triphosphate in vitro

ParB 在 DNA 上的扩散需要体外三磷酸胞苷

• DOI: 10.1101/2019.12.11.865972
• 发表时间: 2019
• 作者: Jalal A