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

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。由于编码信息非常大，因此DNA链非常长。为了将这条线放入细胞的有限空间中，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都具有极其重要的意义，然而人们对这种结构是如何建立和维持的却知之甚少，尤其是在细菌中。这项研究计划旨在了解一种名为新月形茎杆菌的水生细菌中的染色体结构维持蛋白（SMC）是如何折叠染色体的。具体来说，我们的目标是：(i)了解细胞中单个SMC分子在DNA上或断开DNA时的行为；（ii）了解RNA聚合酶如何在染色体上移动SMC； （iii）发现与SMC一起组织细菌染色体的新的相互作用伙伴。有缺陷的凝聚素或凝聚素有助于肿瘤的形成。事实上，在结直肠癌中，有相当一部分癌组织在黏结蛋白或相关基因中存在缺陷。此外，粘接蛋白缺陷被认为是导致遗传性疾病Cornelia deLange综合征的原因。受影响的儿童有缺陷，如缺手指、智力迟钝、生长衰竭、心脏缺陷和其他损伤。我预计，通过使用更简单的活生物体，我对SMC在Caulobacter中的作用的研究将揭示SMC家族蛋白质的古老核心功能，从而提供对人类黏结蛋白和凝血蛋白功能的见解，以及它们的功能障碍如何导致疾病。

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.