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

阐明分枝杆菌中非典型 DNA 错配修复机制

基本信息

批准号：
BB/P007031/1
负责人：
Aidan Doherty
金额：
$ 92.91万
依托单位：
University of Sussex
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%2FP007031%2F1
关键词：
Elucidating mechanism non canonical DNA

项目摘要

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.

我们的细胞包含DNA，即所谓的“生命的遗传蓝图”，它编码我们所有基因的信息。 DNA具有由DNA的两个互补链组成的简单重复结构，该结构由碱基组成，碱基形成构成基因组的长，弦状的双螺旋结构。我们的基因组被包装成几乎每个细胞核中的染色体。该信息必须忠实地复制为细胞分裂以产生子细胞。细胞产生大量蛋白质，负责“影印”此DNA蓝图。精确复制我们遗传代码的数十亿个字母的蛋白质称为DNA复制聚合酶。在此复制过程中，复制机制可以将突变引入新制作的DNA序列，如果未经修复，可以导致疾病状态（例如癌症）的发展。幸运的是，我们的细胞产生修复蛋白，其作用是去除“不匹配”碱基。我们最近发现了一个称为NUC的新型细菌修复基因，发现其产生的蛋白质在帮助细胞在每一轮分裂期间引入的切除突变中起着重要作用，从而确保了有效的基因组复制。在该研究计划中，我们提议确定与细菌细胞中NUC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“何时”以及这些复合物在细胞中工作的位置，定义细胞在细胞中工作，确定删除该修复途径的细胞后果，并最终确定与其他维修范围相处的依据，以确保依赖基因的范围，从而可以依靠这种依赖的范围，从而可以实现这种范围。纠正促进遗传不稳定的有害遗传不匹配突变所需的途径会导致不受控制的细胞生长，从而导致疾病的发作，例如癌症影响细菌突变率的机制和途径将发现新的策略，以预测和打击抗生素耐药性的发展。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle.

DOI：
10.1126/sciadv.abh1004
发表时间：
2021-12-03
期刊：
Science advances
影响因子：
13.6
作者：
Bailey LJ;Teague R;Kolesar P;Bainbridge LJ;Lindsay HD;Doherty AJ
通讯作者：
Doherty AJ

CRISPR-Associated Primase-Polymerases are implicated in prokaryotic CRISPR-Cas adaptation.

DOI：
10.1038/s41467-021-23535-9
发表时间：
2021-06-17
期刊：
Nature communications
影响因子：
16.6
作者：
Zabrady K;Zabrady M;Kolesar P;Li AWH;Doherty AJ
通讯作者：
Doherty AJ

A non-canonical mismatch repair pathway in prokaryotes.

DOI：
10.1038/ncomms14246
发表时间：
2017-01-27
期刊：
Nature communications
影响因子：
16.6
作者：
Castañeda-García A;Prieto AI;Rodríguez-Beltrán J;Alonso N;Cantillon D;Costas C;Pérez-Lago L;Zegeye ED;Herranz M;Plociński P;Tonjum T;García de Viedma D;Paget M;Waddell SJ;Rojas AM;Doherty AJ;Blázquez J
通讯作者：
Blázquez J

Molecular basis for PrimPol recruitment to replication forks by RPA.

DOI：
10.1038/ncomms15222
发表时间：
2017-05-23
期刊：
Nature communications
影响因子：
16.6
作者：
Guilliam TA;Brissett NC;Ehlinger A;Keen BA;Kolesar P;Taylor EM;Bailey LJ;Lindsay HD;Chazin WJ;Doherty AJ
通讯作者：
Doherty AJ

DNA Ligase C and Prim-PolC participate in base excision repair in mycobacteria.

DOI：
10.1038/s41467-017-01365-y
发表时间：
2017-11-01
期刊：
Nature communications
影响因子：
16.6
作者：
Płociński P;Brissett NC;Bianchi J;Brzostek A;Korycka-Machała M;Dziembowski A;Dziadek J;Doherty AJ
通讯作者：
Doherty AJ