NUS Department of Pathology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore.
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
Nucleic Acids Res. 2024 Nov 11;52(20):12351-12377. doi: 10.1093/nar/gkae811.
Mechanisms underlying p53-mediated protection of the replicating genome remain elusive, despite the quintessential role of p53 in maintaining genomic stability. Here, we uncover an unexpected function of p53 in curbing replication stress by limiting PARP1 activity and preventing the unscheduled degradation of deprotected stalled forks. We searched for p53-dependent factors and elucidated RRM2B as a prime factor. Deficiency in p53/RRM2B results in the activation of an NRF2 antioxidant transcriptional program, with a concomitant elevation in basal PARylation in cells. Dissecting the consequences of p53/RRM2B loss revealed a crosstalk between redox metabolism and genome integrity that is negotiated through a hitherto undescribed NRF2-PARP1 axis, and pinpoint G6PD as a primary oxidative stress-induced NRF2 target and activator of basal PARylation. This study elucidates how loss of p53 could be destabilizing for the replicating genome and, importantly, describes an unanticipated crosstalk between redox metabolism, PARP1 and p53 tumor suppressor pathway that is broadly relevant in cancers and can be leveraged therapeutically.
尽管 p53 在维持基因组稳定性方面起着至关重要的作用，但 p53 介导的复制基因组保护的机制仍然难以捉摸。在这里，我们揭示了 p53 的一个意想不到的功能，即通过限制 PARP1 活性和防止未保护的停滞叉的非计划降解来抑制复制应激。我们搜索了依赖 p53 的因子，并阐明了 RRM2B 是主要因子之一。p53/RRM2B 的缺失导致 NRF2 抗氧化转录程序的激活，同时细胞内基础 PARylation 水平升高。剖析 p53/RRM2B 缺失的后果揭示了氧化还原代谢和基因组完整性之间的串扰，这种串扰是通过一个迄今为止尚未描述的 NRF2-PARP1 轴来协商的，并指出 G6PD 是初级氧化应激诱导的 NRF2 靶标和基础 PARylation 的激活剂。这项研究阐明了 p53 的缺失如何使复制基因组不稳定，重要的是，描述了氧化还原代谢、PARP1 和 p53 肿瘤抑制途径之间广泛存在于癌症中的意外串扰，并可以在治疗上加以利用。
