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Defining the role of ADP-ribosyltransferases in DNA repair and genome stability

定义 ADP-核糖基转移酶在 DNA 修复和基因组稳定性中的作用

基本信息

批准号：
MR/P018963/1
负责人：
Nicholas Lakin
金额：
$ 50.37万
依托单位：
University of Oxford
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=MR%2FP018963%2F1
关键词：
Defining role ADP ribosyltransferases DNA

项目摘要

Preserving the integrity of genetic material through repair of damaged DNA is critical for the health of an organism. My laboratory is focussed on understanding these processes, with specific reference to how a set of enzymes called ADP-ribosyltransferases (ARTs) regulate a variety of DNA repair processes.The best defined role of ARTs is in promoting repair of breaks in the DNA double strand helix. Inhibition of this pathway using small molecule ART inhibitors (ARTi) is being exploited in the clinic to specifically kill tumours with defects in a DNA repair process known as homologous recombination. However, there are several different types of ART in a cell and an emerging theme is that these enzymes can regulate different DNA repair processes. The proposed work will build on our recent exciting new findings addressing how different ARTs function together to repair DNA damage and how inhibiting one ART over others more effectively kills cells following exposure to agents that induce DNA damage. Given currently available ARTi target multiple ARTs, these studies will provide information that underpins the development of more specific ARTi with increased efficacy in the clinic. We will also define novel factors that when inhibited along with ARTs either exaggerate or rescue the sensitivity of cells to DNA damage, identifying pathways that make ART inhibited cells more sensitive or tolerant to radio- or chemotherapy. This work will lead to efforts in improving the efficacy of these agents in the clinic and identify new targets whose inhibition will overcome drug resistance.

通过修复受损的DNA来保持遗传物质的完整性对生物体的健康至关重要。我的实验室专注于理解这些过程，特别是一组称为ADP-核糖基转移酶（ART）的酶如何调节各种DNA修复过程。ART的最佳定义作用是促进DNA双链螺旋断裂的修复。临床上正在利用小分子ART抑制剂（阿尔蒂）抑制该途径，以特异性杀死在DNA修复过程（称为同源重组）中存在缺陷的肿瘤。然而，细胞中有几种不同类型的ART，一个新的主题是这些酶可以调节不同的DNA修复过程。拟议的工作将建立在我们最近令人兴奋的新发现的基础上，这些新发现解决了不同的ART如何共同作用以修复DNA损伤，以及如何在暴露于诱导DNA损伤的药物后抑制一种ART更有效地杀死细胞。鉴于目前可用的阿尔蒂靶向多种ART，这些研究将提供信息，支持开发更具特异性的阿尔蒂，提高临床疗效。我们还将定义新的因子，当与ART一起沿着抑制时，这些因子会夸大或挽救细胞对DNA损伤的敏感性，确定使ART抑制的细胞对放疗或化疗更敏感或耐受的途径。这项工作将导致努力提高这些药物在临床上的疗效，并确定新的目标，其抑制将克服耐药性。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption.

DOI：
10.1038/s41467-023-40779-9
发表时间：
2023-08-17
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Sharma, Abhishek Bharadwaj;Ramlee, Muhammad Khairul;Kosmin, Joel;Higgs, Martin R.;Wolstenholme, Amy;Ronson, George E.;Jones, Dylan;Ebner, Daniel;Shamkhi, Noor;Sims, David;Wijnhoven, Paul W. G.;Forment, Josep;Gibbs-Seymour, Ian;Lakin, Nicholas D.
通讯作者：
Lakin, Nicholas D.

PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation.

DOI：
10.1038/s41467-018-03159-2
发表时间：
2018-02-21
期刊：
Nature communications
影响因子：
16.6
作者：
Ronson GE;Piberger AL;Higgs MR;Olsen AL;Stewart GS;McHugh PJ;Petermann E;Lakin ND
通讯作者：
Lakin ND

PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation

PARP1 和 PARP2 通过 Fbh1 依赖性 Rad51 调节稳定碱基切除修复中间体的复制叉

DOI：
10.1101/243071
发表时间：
2018
期刊：
影响因子：
0
作者：
Ronson G
通讯作者：
Ronson G

Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3.

DOI：
10.1038/s41467-023-40071-w
发表时间：
2023-07-18
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Richards, Frederick;Llorca-Cardenosa, Marta J.;Langton, Jamie;Buch-Larsen, Sara C.;Shamkhi, Noor F.;Sharma, Abhishek Bharadwaj;Nielsen, Michael L.;Lakin, Nicholas D.
通讯作者：
Lakin, Nicholas D.

Dictyostelium discoideum as a Model to Assess Genome Stability Through DNA Repair.

DICTyostelium Discoideum作为通过DNA修复评估基因组稳定性的模型。