p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways

eLife

Sunetra Roy¹  Katharina Schlacher¹  Karl-Heinz Tomaszowski¹  Soyoung Park¹  Jessica W Luzwick¹  Jun Li²  Maureen Murphy³ 

[1] Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, United States;Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, United States;Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, United States;

关键词: p53;    genome instability;    replication fork restart;    MRE11;    BRCA2;    replication protection;   

DOI  :  10.7554/eLife.31723

来源: DOAJ

【 摘 要 】

Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks that drive genomic instability, which isgenetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53-mediated suppression of replication genome instability.

【 授权许可】

Unknown