Defining the role of PARPs in the DNA repair and genome stability

定义 PARP 在 DNA 修复和基因组稳定性中的作用

• 批准号: MR/V00896X/1
• 负责人: Nicholas Lakin
• 金额: $ 102.01万
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV00896X%2F1
• 关键词: Defining; role; PARPs; DNA; repair

Preserving the integrity of genetic material through repair of damaged DNA is critical for the health of an organism. DNA repair mechanisms that resolve different DNA lesions are becoming increasingly well defined. However, a remaining challenge is to understand how these processes integrate to allow cell survival if a particular repair pathway fails. Deciphering these complex interactions will define the mechanistic basis of genome stability and uncover strategies to manipulate these pathways for clinical benefit. My laboratory is focussed on addressing these important questions, with specific reference to how a set of enzymes called Poly(ADP-ribose)-polymerases (PARPs) regulate DNA repair.The best defined role of PARPs is in promoting repair of breaks in the DNA double strand helix. Inhibition of this pathway using small molecule PARP inhibitors (PARPi) is being exploited in the clinic to kill tumours with defects in a DNA repair process known as homologous recombination (HR). Our current understanding of this process is that PARPi can 'trap' two enzymes, PARP1 and PARP2 at DNA breaks. These PARP-DNA adducts then blocks enzymes that copy genetic material during DNA replication, causing DNA damage that requires HR for repair. Therefore, in the absence of HR, cells are killed due to their inability to repair PARPi-induced replication blocks. Importantly, our previous MRC funded work indicated that there is significant functional overlap in these mechanisms and that PARP1/PARP2 not only promote repair of DNA breaks, but also resolution of replication blocks. The proposed work will build on these key conceptual advances in addition to exciting new data from my laboratory to further define how PARPs promote genome integrity. Specifically, we will characterise an additional PARP-dependent mechanism to repair replication blocks, in addition to a novel gene that can compensate for loss of PARP1/PARP2.These studies will not only increase our understanding of fundamental principles that allow cells to maintain genome integrity, but also provide critical information that will underpin development more specific PARPi with increased efficacy in the clinic. Moreover, identifying genes that are critical for cell viability when PARPs are disrupted will identify strategies to broaden the use of these agents to treat tumour types with defects in pathways other than HR.

通过修复受损DNA来保持遗传物质的完整性对生物体的健康至关重要。解决不同DNA损伤的DNA修复机制正变得越来越明确。然而，一个剩下的挑战是理解这些过程是如何整合在一起的，如果一个特定的修复途径失败，细胞存活。破译这些复杂的相互作用将定义基因组稳定性的机制基础，并揭示为临床利益操纵这些途径的策略。我的实验室专注于解决这些重要问题，具体涉及一组称为聚（adp -核糖）-聚合酶（PARPs）的酶如何调节DNA修复。PARPs最明确的作用是促进DNA双链螺旋断裂的修复。在临床上，利用小分子PARP抑制剂（PARPi）来抑制这一途径，以杀死在称为同源重组（HR）的DNA修复过程中存在缺陷的肿瘤。我们目前对这一过程的理解是，PARPi可以在DNA断裂处“捕获”两种酶，PARP1和PARP2。这些PARP-DNA加合物阻断了DNA复制过程中复制遗传物质的酶，导致DNA损伤，需要HR来修复。因此，在缺乏HR的情况下，细胞由于无法修复parpi诱导的复制阻滞而被杀死。重要的是，我们之前MRC资助的工作表明，这些机制中存在显著的功能重叠，PARP1/PARP2不仅促进DNA断裂的修复，而且还促进复制块的分解。拟议的工作将建立在这些关键的概念进展之上，以及来自我实验室的令人兴奋的新数据，以进一步定义parp如何促进基因组完整性。具体来说，我们将描述一个额外的parp依赖机制来修复复制块，以及一个可以补偿PARP1/PARP2缺失的新基因。这些研究不仅将增加我们对细胞维持基因组完整性的基本原理的理解，而且还将提供关键信息，为开发更具体的PARPi提供基础，提高临床疗效。此外，当parp被破坏时，识别对细胞活力至关重要的基因将确定策略，以扩大这些药物的使用，以治疗除HR以外的途径中存在缺陷的肿瘤类型。

项目成果

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.

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.