Elucidating the mechanism of non-canonical DNA mismatch repair in mycobacteria

我们的细胞含有DNA，即所谓的“生命的遗传蓝图”，它为我们所有的基因编码信息。DNA具有简单的重复结构，由两条互补的DNA链组成，这些DNA链由碱基组成，它们形成长的、线状的双螺旋结构，构成基因组。我们的基因组被包装成染色体，包含在几乎每个细胞的细胞核中。当细胞分裂产生子细胞时，这些信息必须被忠实地复制。细胞产生大量的蛋白质，负责“影印”这一DNA蓝图。负责精确复制我们遗传密码中数十亿个字母的蛋白质被称为DNA复制聚合酶。在这个复制过程中，复制机制可以将突变引入新产生的DNA序列，如果不修复，可能导致疾病状态的发展，如癌症。幸运的是，我们的细胞产生修复蛋白，其作用是去除“错配”碱基。我们最近发现了一种名为NucS的新型细菌修复基因，并发现它产生的蛋白质在帮助细胞切除每一轮细胞分裂期间引入的突变方面起着重要作用，从而确保有效的基因组复制。在这项研究计划中，我们建议确定细菌细胞中与NucS一起工作的其他蛋白质，确定这些修复机器如何能够去除和纠正DNA突变，确定这些复合物在细胞中“何时”和“何地”运作，定义删除这种修复途径的细胞后果，最后确定它是否与其他修复途径合作以确保基因组稳定性。该提案将为纠正有害的基因错配突变所需的基本突变避免途径提供重要见解。突变的过度积累可能导致细胞生长失控，从而导致疾病的发生，如癌症。然而，在原核生物中，它可以导致主要病原菌的抗生素耐药性的发展。抗生素耐药性的上升已被确定为全球健康面临的主要威胁之一。因此，了解影响细菌突变率的基本机制和途径将揭示预测和对抗抗生素耐药性发展的新策略。

Our cells contain DNA, the so called "genetic blueprint of life", which encodes the information for all our genes. DNA has a simple repeating structure composed of two complementary strands of DNA composed of bases, which form long, string-like, double-helix structures that make up the genome. Our genome is packaged away into chromosomes, contained within the nucleus of nearly every cell. This information must be faithfully copied as cells divide to produce daughter cells. Cells produce a large number of proteins responsible for "photocopying" this DNA blueprint. The proteins tasked with accurately copying the several billion letters of our genetic code are called DNA replication polymerases. During this copying process, the replication machinery can introduce mutations to the newly made DNA sequence that can, if left unrepaired, lead to the development of disease states, such as cancer. Fortunately, our cells produce repair proteins whose role it is to remove the "mismatched" bases. We have recently discovered a novel bacterial repair gene called NucS and discovered that the protein it produces plays an important role in helping cells to excise mutations introduced during every round of cell division thus ensuring efficient genome replication. In this research programme, we are proposing to identify additional proteins that operate with NucS in the bacterial cell, determine how these repair machines are able to remove and correct DNA mutations, identify "when" and where" these complexes operate in cells, define the cellular consequences of deleting this repair pathway and, finally, determine if it co-operates with other repair pathways to ensure genome stability. This proposal will provide critical insights into a fundamental mutation avoidance pathway required to correct harmful genetic mismatch mutations that promote genetic instability.Excessive accumulation of mutations can lead to uncontrolled cell growth that can result in the onset of diseases, such as cancer. However, in prokaryotes it can lead to the development of antibiotic resistance in major pathogenic bacteria. The rise of antibiotic resistance has been identified as one of the major threats facing global health. Therefore, understanding fundamental mechanisms and pathways that influence mutation rates in bacteria will uncover new strategies to predict and combat the development of antibiotic resistance.