The essential link between DNA repair and cell wall synthesis in bacteria

细菌太小了，没有显微镜就看不见，但它们数量众多，无处不在，对我们的生活影响巨大。人类分享我们的身体与大量和非常不同种类的细菌，在我们身体的不同部位茁壮成长。虽然有些细菌对环境和我们的健康有益，但有些细菌会引起疾病，从小伤口感染到腹泻，再到败血症和肺炎等致命疾病。作为地球上最早的生命形式之一，细菌是健壮的，并且已经进化到能够在不同的环境中生存和繁殖。位于细菌细胞膜外部的细胞壁保护细菌免受不利环境条件的影响，并防止细胞因其高内部压力而破裂。当细菌繁殖时，承受压力的细胞壁需要以这样一种方式扩张，即新的细胞壁材料被合成并编织到现有的细胞壁中，而不会在此过程中削弱或损坏细胞壁。损害细胞壁的完整性将导致细胞通过裂解而死亡。我们的许多最好的抗生素，例如，青霉素通过抑制细胞壁的合成来杀死细菌。除了强大而充满活力的细胞壁外，为了产生健康的后代，细胞还需要复制其染色体而没有错误，然后在细胞分裂之前将两个姐妹染色体分配到细胞中的适当位置。复制过程中发生的所有错误和任何损伤都必须得到修复，以便子细胞继承的染色体保持完整。因此，保持染色体的完整性和保持细胞壁的完整性对细菌来说都是必不可少的。然而，它们被认为是独立的过程，并且不知道它们是连接的。最近，我们惊讶和兴奋地发现这两个看似无关的过程之间存在一些潜在的联系：1）细胞壁合成基因ponA的突变体，已知具有“更薄”的细胞，表现出染色体缺陷; 2）在许多细菌中，ponA基因位于染色体上，与称为recU的染色体修复基因形成“簇”。通常形成簇的基因具有相关的功能，并且在如此多的细菌中，细胞壁合成基因与DNA修复基因如此紧密地相关，表明这两个基因之间存在功能联系。3)去除ponA或recU不会影响细胞的活力，但去除这两个基因是致命的。这是令人困惑但有趣的，因为它再次表明染色体修复和细胞壁合成以某种方式连接。4)许多细菌都有第二组基因，其中包含一个参与染色体修复（针对不同类型的损伤）的基因和一个参与细胞壁代谢的基因。这表明染色体修复和细胞壁合成可能有多个环节。该提案旨在调查和了解染色体修复和细胞壁合成之间的潜在联系。我们想知道这些联系是如何介导的，细胞宽度和受损的细胞壁合成对染色体修复和分布的影响，以及DNA损伤如何影响细胞壁。对染色体-细胞壁连接的分子理解将有助于我们确定抗生素的新靶点，并开发新的抗菌策略，以优化现有抗生素的使用并对抗抗生素耐药性。

Bacteria are too small to be seen without a microscope, but they are abundant and ubiquitous and, their influence on our life is enormous. Humans share our body with a large number and a very diverse number of species of bacteria that thrive in/on different parts of our body. While some of the bacteria are beneficial for the environment and for our health, some cause diseases, from small wound infections, to diarrhoea to lethal diseases such as sepsis and pneumonia. Being one of the earliest life forms on earth, bacteria are robust and have evolved to be able to survive and propagate in different environments. The cell wall that is located outside of the bacterial cell membrane protects bacteria from adverse environmental conditions and also prevents the cell from bursting due to its high internal pressure. When bacteria propagate, the stress-bearing cell wall needs to expand in such a way that the new cell wall material is synthesised and woven into the existing wall without weakening or damaging the wall in the process. Compromising the integrity of the cell wall will lead to cell death by lysis. Many of our best antibiotics, e.g., penicillin, kill bacteria by inhibiting cell wall synthesis. In addition to a strong yet dynamic cell wall, to produce fit and healthy progeny the cell also needs to duplicate its chromosome without mistakes and then partition the two sister chromosomes to the appropriate positions in the cell before cell division. It is essential that all mistakes and any damage that occurs during the process of duplication are repaired so that the chromosomes inherited by the daughter cells are intact. Therefore, maintaining the integrity of the chromosome and maintaining the integrity of the cell wall are both essential for bacteria. However, they are considered independent processes and are not known to be connected. Recently we were surprised and excited to discover some potential links between these two seemingly unrelated processes: 1) Mutants of the cell wall synthesis gene ponA, which is known to have 'thinner' cells, exhibit chromosome defects; 2) In many bacteria the ponA gene is located on the chromosome in a 'cluster' with a chromosome repair gene called recU. Normally genes forming a cluster have related functions, and a cell wall synthesis gene being so tightly associated with a DNA repair gene, in so many bacteria, suggests a functional link between these two genes. 3) Removal of either ponA or recU does not affect the viability of the cell, but removing both genes is lethal. This is puzzling but interesting as it again indicates that chromosome repair and cell wall synthesis are somehow connected. 4) Many bacteria have a second cluster of genes that contain a gene involved in chromosome repair (for a different type of damage) and genes involved in cell wall metabolism. This suggests that chromosome repair and cell wall synthesis may have multiple links. This proposal aims to investigate and understand the potential links between chromosome repair and cell wall synthesis. We want to know how the links are mediated, the impacts of cell width and impaired cell wall synthesis on chromosome repair and distribution, and how DNA damage affects the cell wall. A molecular understanding of the chromosome - cell wall links will help us identify new targets for antibiotics, and develop new antimicrobial strategies to optimise the use of the existing antibiotics and combat antibiotics resistance.