Cell cycle regulation of the NHEJ DNA double-strand break repair pathway in eukaryotes

真核生物 NHEJ DNA 双链断裂修复途径的细胞周期调控

基本信息

批准号：
BB/M004236/1
负责人：
Aidan Doherty
金额：
$ 81.07万
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：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM004236%2F1
关键词：
Cell cycle regulation NHEJ DNA

项目摘要

Our cells contain DNA, the so called "genetic blueprint of life" which encodes the information for our genes. DNA has a simple repeating structure composed of two complementary strands of DNA, which form a double-helix structure. The integrity of DNA is constantly being challenged by various DNA-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 attack and damage DNA. In recent years, it has been realised that our own cells produce a large number of different proteins responsible for repairing this DNA damage which, if left unchecked, would lead to the destabilization of our genomic DNA. It is now recognized that genome instability is one of the major drivers for the development of major human diseases, such as cancer. These protein "machines" can cut out and replace aberrant DNA mutations/structures and splice together broken DNA strands. One such machine is the non homologous end-joining (NHEJ) DNA break repair complex. This repair apparatus is able to detect physical breaks in the DNA helices, bring the ends back together, remodel them if required and, finally, reseal these breaks to restore the continuity of the double-strand DNA. However, if unregulated, an over abundance of these repair machines could potentially also have dangerous consequences by interfering with normal cell processes, such as DNA replication and cell division. The focus of this proposal is to understand how our cells control these repair complexes to ensure they are available when required but, importantly, switched off when they are likely to be harmful to the cell.

我们的细胞包含DNA，即所谓的“生命的遗传蓝图”，它编码了我们基因的信息。 DNA具有简单的重复结构，该结构由DNA的两个互补链组成，该结构形成双螺旋结构。 DNA的完整性不断受到各种DNA损害剂的挑战。这些试剂包括来自太阳的高能量紫外线和X射线辐射，化学物质（人造和环境），甚至我们呼吸的氧气都会攻击和损坏DNA。近年来，已经意识到我们自己的细胞会产生大量负责修复这种DNA损伤的不同蛋白质，如果不受组织检查，这将导致我们的基因组DNA稳定。现在已经认识到，基因组不稳定性是主要人类疾病（例如癌症）发展的主要驱动因素之一。这些蛋白质“机器”可以切出并替换异常的DNA突变/结构，并剪接碎DNA链。这样的机器是非同源最终连接（NHEJ）DNA断裂修复复合物。该修复设备能够检测到DNA螺旋中的物理断裂，将末端重新恢复，如果需要，将它们重塑，最后重新密封这些断裂以恢复双链DNA的连续性。但是，如果不监管，这些修复机器过度的丰度也可能会通过干扰正常的细胞过程（例如DNA复制和细胞分裂）而产生危险的后果。该提案的重点是了解我们的单元如何控制这些修复复合物，以确保它们在需要时可用，但重要的是，当它们可能对细胞有害时关闭。

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）

Cdk1 restrains NHEJ through phosphorylation of XRCC4-like factor Xlf1.

DOI：
10.1016/j.celrep.2014.11.044
发表时间：
2014-12-24
期刊：
Cell reports
影响因子：
8.8
作者：
Hentges P;Waller H;Reis CC;Ferreira MG;Doherty AJ
通讯作者：
Doherty AJ

Primase-polymerases are a functionally diverse superfamily of replication and repair enzymes.

DOI：
10.1093/nar/gkv625
发表时间：
2015-08-18
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Guilliam TA;Keen BA;Brissett NC;Doherty AJ
通讯作者：
Doherty AJ

PolDIP2 interacts with human PrimPol and enhances its DNA polymerase activities.

DOI：
10.1093/nar/gkw175
发表时间：
2016-04-20
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Guilliam TA;Bailey LJ;Brissett NC;Doherty AJ
通讯作者：
Doherty AJ

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