Understanding the role of ADP-ribosylation in regulating DNA repair

了解 ADP-核糖基化在调节 DNA 修复中的作用

• 批准号: 2105259
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2105259
• 关键词: Understanding; role; ADP; ribosylation; regulating

The human genome is under frequent attack from a number of exogenous and endogenous sources of DNA damage which can threaten genome integrity and cause genome instability. In order to mitigate the negative effects of DNA damage, human cells have evolved a range of protective mechanisms to resolve DNA lesions. Collectively, these pathways are known as the DNA damage response (DDR). Poly (ADP-ribose) polymerases (PARPs) are a superfamily of 17 proteins with a variety of cellular functions, and PARP1 and 2 are known to play important roles in single strand break repair (SSBR). However, the roles of additional PARPs in this pathway are relatively ill-defined. PARP inhibitors (PARPi) are used in the clinic to treat patients with chemo-resistant ovarian cancer, but their clinical efficacy may be reduced by not targeting all of the PARPs involved in SSBR. By further exploring the functional roles of PARPs in the DDR, we aim to pave the way for the development of novel PARP inhibitors that target specific PARPs and have greater clinical efficacy. This proposed research addresses the healthy ageing across lifecourse BBSRC priority area and aligns with the Bisocience for Health DTP priority area. BfH, WCUB, ENWW

人类基因组经常受到许多外源性和内源性DNA损伤源的攻击，这些DNA损伤源可能威胁基因组的完整性并导致基因组不稳定。为了减轻DNA损伤的负面影响，人类细胞已经进化出一系列保护机制来解决DNA损伤。这些途径统称为DNA损伤反应（DDR）。聚腺苷二磷酸核糖聚合酶（Poly（ADP-ribose）polymerases，PARP）是一个由17个蛋白质组成的超家族，具有多种细胞功能，其中PARP 1和PARP 2在单链断裂修复（single strand break repair，SSBR）中发挥重要作用。然而，额外的PARP在该途径中的作用相对不明确。PARP抑制剂（PARPi）在临床上用于治疗化疗耐药卵巢癌患者，但其临床疗效可能会因不靶向SSBR中涉及的所有PARP而降低。通过进一步探索PARP在DDR中的功能作用，我们的目标是为开发靶向特定PARP并具有更大临床疗效的新型PARP抑制剂铺平道路。这项拟议的研究涉及整个生命周期的健康老龄化BBSRC优先领域，并与Bisoscience for Health DTP优先领域保持一致。BfH、WCUB、ENWW