Molecular and cellular mechanisms utilized by Primase-Polymerase centric DNA repair pathways during stationary phase in mycobacteria

我们细胞的DNA，即所谓的“生命的遗传蓝图”，为我们所有的基因编码信息。DNA有一个简单的重复结构，由两条互补的DNA链组成，这些DNA链由碱基组成，形成了长串状的双螺旋结构，构成了基因组。我们的基因组被打包成染色体，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。细胞产生大量负责“复印”DNA蓝图的蛋白质。负责精确复制我们遗传密码几十亿个字母的蛋白质被称为DNA聚合酶。在这个复制过程中，复制机制可以将突变引入新生成的DNA序列，如果不进行修复，就会导致疾病状态的发展，比如癌症。DNA的完整性也不断受到各种破坏因子的挑战。这些因素包括来自太阳的高能紫外线和x射线辐射、化学物质——无论是人造的还是环境的——甚至我们呼吸的氧气都能破坏DNA。幸运的是，我们的细胞产生修复蛋白，其作用是去除“受损”的碱基。我们最近发现了一种新的细菌DNA修复“机器”，它在切除和修复这些“有毒”突变中起着重要作用，从而确保基因组的稳定性，并最终确保细胞的存活。在这项研究计划中，我们建议确定这些修复机器如何检测、移除和纠正DNA突变，确定删除这条修复途径的细胞后果，最后确定它是否与其他相关的修复途径合作以确保基因组稳定。这一建议将为纠正促进细菌病原体遗传不稳定的有害基因突变所需的基本DNA修复途径提供关键见解。损伤的过度积累会导致不受控制的细胞生长，从而导致癌症等疾病的发作。然而，在细菌中，它会导致主要致病菌产生抗生素耐药性。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发现预测和对抗抗生素耐药性发展的新策略。

Our cells DNA, the so called "genetic blueprint of life", 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-helical 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 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. The integrity of DNA is also constantly being challenged by various damaging agents. These agents include high energy UV and X-ray radiation from the sun, chemicals - both man-made and environmental - and even the oxygen we breathe can damage DNA. Fortunately, our cells produce repair proteins whose role it is to remove the "damaged" bases. We have recently discovered a novel bacterial DNA repair "machine" that plays an important role in excising and repairing these "toxic" mutations thus ensuring genome stability and, ultimately, cell survival. In this research programme, we are proposing to determine how these repair machines detect, remove and correct DNA mutations, define the cellular consequences of deleting this repair pathway and, finally, determine if it co-operates with other related repair pathways to ensure genome stability. This proposal will provide critical insights into a fundamental DNA repair pathway required to correct harmful genetic mutations that promote genetic instability in bacterial pathogens.Excessive accumulation of damage can lead to uncontrolled cell growth that can result in the onset of diseases, such as cancer. However, in bacteria 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.