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

点击翻译按钮获取中文摘要

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.