p53-dependent crosstalk between DNA replication integrity and redox metabolism mediated through a NRF2-PARP1 axis

Nucleic Acids Res. 2024 Nov 11;52(20):12351-12377. doi: 10.1093/nar/gkae811.

Abstract

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.

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • DNA Replication*
  • Genomic Instability / genetics
  • Humans
  • Mice
  • NF-E2-Related Factor 2* / genetics
  • NF-E2-Related Factor 2* / metabolism
  • Oxidation-Reduction*
  • Oxidative Stress
  • Poly (ADP-Ribose) Polymerase-1* / genetics
  • Poly (ADP-Ribose) Polymerase-1* / metabolism
  • Ribonucleotide Reductases
  • Signal Transduction
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Poly (ADP-Ribose) Polymerase-1
  • Tumor Suppressor Protein p53
  • NF-E2-Related Factor 2
  • PARP1 protein, human
  • RRM2B protein, human
  • NFE2L2 protein, human
  • TP53 protein, human
  • Ribonucleotide Reductases
  • Cell Cycle Proteins

Grants and funding