p53 suppresses mutagenic RAD52 and POLθ pathways by orchestrating DNA replication restart homeostasis

  1. Sunetra Roy
  2. Karl-Heinz Tomaszowski
  3. Jessica W Luzwick
  4. Soyoung Park
  5. Jun Li
  6. Maureen Murphy
  7. Katharina Schlacher  Is a corresponding author
  1. UT MD Anderson Cancer Center, United States
  2. 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

The following previously published data sets were used
    1. The Cancer Genome Atlas Research Network
    (2016) Breast Cancer TCGA dataset (TCGA-BRCA)
    Publicly available from the NCI GDC Data Portal (https://cancergenome.nih.gov).

Article and author information

Author details

  1. Sunetra Roy

    Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, United States
    Competing interests
    No competing interests declared.
  2. Karl-Heinz Tomaszowski

    Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, United States
    Competing interests
    No competing interests declared.
  3. Jessica W Luzwick

    Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, United States
    Competing interests
    No competing interests declared.
  4. Soyoung Park

    Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, United States
    Competing interests
    No competing interests declared.
  5. Jun Li

    Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, United States
    Competing interests
    No competing interests declared.
  6. Maureen Murphy

    Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, United States
    Competing interests
    Maureen Murphy, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7644-7296
  7. Katharina Schlacher

    Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, United States
    For correspondence
    KSchlacher@mdanderson.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7226-6391

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.

Reviewing Editor

  1. Simon Powell, Memorial Sloan Kettering Cancer Center, United States

Version history

  1. Received: September 3, 2017
  2. Accepted: January 12, 2018
  3. Accepted Manuscript published: January 15, 2018 (version 1)
  4. Version of Record published: March 1, 2018 (version 2)

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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  1. Sunetra Roy
  2. Karl-Heinz Tomaszowski
  3. Jessica W Luzwick
  4. Soyoung Park
  5. Jun Li
  6. Maureen Murphy
  7. Katharina Schlacher
(2018)
p53 suppresses mutagenic RAD52 and POLθ pathways by orchestrating DNA replication restart homeostasis
eLife 7:e31723.
https://doi.org/10.7554/eLife.31723

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https://doi.org/10.7554/eLife.31723