Cell cycle control of DNA double strand break repair and the role of Cdk

DNA双链断裂修复的细胞周期调控及Cdk的作用

• 批准号: BB/H003371/1
• 负责人: Andrew Porter
• 金额: $ 40.35万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH003371%2F1
• 关键词: Cell; cycle; control; DNA; double

Our genetic material is subject to damage: double-stranded DNA can become broken in both strands, fracturing chromosomes. Such double-stand breaks (DSBs) must be repaired as accurately as possible; failed or incorrectly controlled repair will lead to scrambling of the genetic material and contribute to the development of genetic disease, including cancer, and to the ageing process. Understanding the repair processes is also important because many biotechnological and therapeutic techniques involve delivering DNA to cells, and the fate of this DNA is determined by the cells' DSB repair machinery. It is proposed here to investigate how the two main cellular mechanisms for repairing DSBs are controlled as cells grow, duplicate and divide. The choice between the two main repair mechanisms (called NHEJ and HRR) is determined by the position of the 'cell cycle': before cells have replicated their genetic material NHEJ predominates, but during and after replication the two pathways coexists, although there is debate over the relative amounts. Regulator proteins that control the timing of DNA replication and division (called cyclin dependent kinases; Cdks) also regulate the choice between HRR and NHEJ. Cdk activity can promote or inhibit HRR at the expense of NHEJ, but is not clear exactly how, when in the cell cycle or which particular type of Cdk does what. We will develop new and improved methods to measure HRR and NHEJ at different stages of the cell cycle, and determine how two particular Cdks, Cdk1 and Cdk2 are involved.

我们的遗传物质会受到损害：双链 DNA 的两条链都会断裂，从而导致染色体断裂。必须尽可能准确地修复此类双支架断裂 (DSB)；失败或错误控制的修复将导致遗传物质的混乱，并导致遗传疾病（包括癌症）的发展以及衰老过程。了解修复过程也很重要，因为许多生物技术和治疗技术都涉及将 DNA 传递到细胞，而这种 DNA 的命运是由细胞的 DSB 修复机制决定的。本文建议研究当细胞生长、复制和分裂时如何控制修复 DSB 的两种主要细胞机制。两种主要修复机制（称为 NHEJ 和 HRR）之间的选择取决于“细胞周期”的位置：在细胞复制其遗传物质之前，NHEJ 占主导地位，但在复制期间和复制后，这两种途径共存，尽管对相对数量存在争议。控制 DNA 复制和分裂时间的调节蛋白（称为细胞周期蛋白依赖性激酶；Cdks）也调节 HRR 和 NHEJ 之间的选择。 Cdk 活性可以以 NHEJ 为代价促进或抑制 HRR，但尚不清楚具体如何、何时处于细胞周期或哪种特定类型的 Cdk 发挥作用。我们将开发新的和改进的方法来测量细胞周期不同阶段的 HRR 和 NHEJ，并确定两个特定的 Cdks（Cdk1 和 Cdk2）如何参与其中。

项目成果

A role for human homologous recombination factors in suppressing microhomology-mediated end joining.

• DOI: 10.1093/nar/gkw326
• 发表时间: 2016-07-08
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Ahrabi S;Sarkar S;Pfister SX;Pirovano G;Higgins GS;Porter AC;Humphrey TC
• 通讯作者: Humphrey TC

SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability.

• DOI: 10.1016/j.celrep.2014.05.026
• 发表时间: 2014-06-26
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Pfister SX;Ahrabi S;Zalmas LP;Sarkar S;Aymard F;Bachrati CZ;Helleday T;Legube G;La Thangue NB;Porter AC;Humphrey TC
• 通讯作者: Humphrey TC

Use of the HPRT gene to study nuclease-induced DNA double-strand break repair.

• DOI: 10.1093/hmg/ddv409
• 发表时间: 2015-12-15
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Gravells P;Ahrabi S;Vangala RK;Tomita K;Brash JT;Brustle LA;Chung C;Hong JM;Kaloudi A;Humphrey TC;Porter AC
• 通讯作者: Porter AC