p53 suppresses mutagenic RAD52 and POLθ pathways by orchestrating DNA replication restart homeostasis
- UT MD Anderson Cancer Center, United States
- The Wistar Institute, United States
Abstract
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 driving genomic instability genetically 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 POLq 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.
Data availability
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Breast Cancer TCGA dataset (TCGA-BRCA)Publicly available from the NCI GDC Data Portal (https://cancergenome.nih.gov).
Article and author information
Author details
Katharina Schlacher
Funding
Cancer Prevention and Research Institute of Texas (R1312)
- Katharina Schlacher
National Cancer Institute (K22CA175262)
- Katharina Schlacher
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Roy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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p53 suppresses mutagenic RAD52 and POLθ pathways by orchestrating DNA replication restart homeostasis
eLife 7:e31723.
https://doi.org/10.7554/eLife.31723
