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Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

Panagiotis Galanos1,2, George Pappas1,2, Alexander Polyzos3

  • 1Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, 75 Mikras Asias Str, GR-11527, Athens, Greece.

Genome Biology
|March 18, 2018
PubMed
Abstract

Insights

Chronic p21 expression in p53-deficient tumors fuels genomic instability by impairing DNA repair. This leads to increased DNA double-strand breaks (DSBs) and identifies Rad52 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genomic instability is a hallmark of cancer, driving tumor evolution and heterogeneity.
  • Previous work identified chronic p21 expression in p53-deficient cells as a driver of genomic instability via replication licensing deregulation.
  • Understanding the mechanisms of genomic instability is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the role of p21 in DNA repair pathways.
  • To elucidate the mechanisms by which p21 contributes to genomic instability.
  • To identify potential therapeutic targets for cancers with genomic instability.

Main Methods:

  • Analysis of DNA repair pathway capacity in cells with chronic p21 expression.
  • Characterization of mutational signatures to infer DNA repair processes.
  • Investigation of Rad52 activation mechanisms.
  • Assessment of E2F1's role in Rad52 regulation.

Main Results:

  • Chronic p21 expression suppresses both low- and high-fidelity DNA repair pathways for nucleotide abnormalities.
  • This suppression results in decreased single nucleotide substitutions (SNSs) and increased DNA double-strand breaks (DSBs).
  • DNA double-strand breaks are repaired via Rad52-dependent pathways (BIR and SSA), while error-free SDSA is deficient.
  • Rad52 is activated transcriptionally in an E2F1-dependent manner, differing from typical post-translational activation.

Conclusions:

  • Mutational signatures are valuable tools for understanding the repair history contributing to genomic instability.
  • Chronic p21 expression fundamentally alters DNA repair processes, promoting genomic instability.
  • Rad52 is identified as a key mediator of genomic instability and a potential therapeutic target.
Keywords:
Break-induced replication (BIR)Genomic instabilityRad52Single nucleotide substitution (SNS)Single strand annealing (SSA)Translesion DNA synthesis (TLS)p21WAF1/Cip1

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