Understanding the role of ADP-ribosylation in regulating DNA repair

人类基因组经常受到许多外源和内源DNA损伤的攻击，这些损伤可以威胁基因组的完整性，并导致基因组的不稳定。为了减轻DNA损伤的负面影响，人类细胞进化出了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)。多聚(ADP-核糖)聚合酶(PARP)是一个由17种蛋白质组成的超家族，具有多种细胞功能，其中PARP1和PAR2在单链断裂修复(SSBR)中起重要作用。然而，额外的PAP在这一途径中的作用相对来说还不清楚。PARP抑制剂(PARPI)在临床上用于治疗化疗耐药的卵巢癌患者，但由于不针对SSBR中涉及的所有PARP，其临床疗效可能会降低。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针对特定PARP并具有更高临床疗效的新型PARP抑制剂铺平道路。这项拟议的研究涉及生命周期BBSRC优先领域的健康老龄化，并与Biscience for Health DTP优先领域保持一致。BFH、WCUB、ENWW

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