Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability. Academic Article uri icon

Overview

abstract

  • BACKGROUND: Genomic instability promotes evolution and heterogeneity of tumors. Unraveling its mechanistic basis is essential for the design of appropriate therapeutic strategies. In a previous study, we reported an unexpected oncogenic property of p21WAF1/Cip1, showing that its chronic expression in a p53-deficient environment causes genomic instability by deregulation of the replication licensing machinery. RESULTS: We now demonstrate that p21WAF1/Cip1 can further fuel genomic instability by suppressing the repair capacity of low- and high-fidelity pathways that deal with nucleotide abnormalities. Consequently, fewer single nucleotide substitutions (SNSs) occur, while formation of highly deleterious DNA double-strand breaks (DSBs) is enhanced, crafting a characteristic mutational signature landscape. Guided by the mutational signatures formed, we find that the DSBs are repaired by Rad52-dependent break-induced replication (BIR) and single-strand annealing (SSA) repair pathways. Conversely, the error-free synthesis-dependent strand annealing (SDSA) repair route is deficient. Surprisingly, Rad52 is activated transcriptionally in an E2F1-dependent manner, rather than post-translationally as is common for DNA repair factor activation. CONCLUSIONS: Our results signify the importance of mutational signatures as guides to disclose the repair history leading to genomic instability. We unveil how chronic p21WAF1/Cip1 expression rewires the repair process and identifies Rad52 as a source of genomic instability and a candidate therapeutic target.

authors

  • Galanos, Panagiotis
  • Pappas, George
  • Polyzos, Alexander
  • Kotsinas, Athanassios
  • Svolaki, Ioanna
  • Giakoumakis, Nickolaos N
  • Glytsou, Christina
  • Pateras, Ioannis S
  • Swain, Umakanta
  • Souliotis, Vassilis L
  • Georgakilas, Alexandros G
  • Geacintov, Nicholas
  • Scorrano, Luca
  • Lukas, Claudia
  • Lukas, Jiri
  • Livneh, Zvi
  • Lygerou, Zoi
  • Chowdhury, Dipanjan
  • Sørensen, Claus Storgaard
  • Bartek, Jiri
  • Gorgoulis, Vassilis G

publication date

  • March 16, 2018

Research

keywords

  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA Repair
  • Genomic Instability
  • Mutation
  • Rad52 DNA Repair and Recombination Protein
  • Tumor Suppressor Protein p53

Identity

PubMed Central ID

  • PMC5857109

Scopus Document Identifier

  • 85043983198

Digital Object Identifier (DOI)

  • 10.1101/cshperspect.a016436

PubMed ID

  • 29548335

Additional Document Info

volume

  • 19

issue

  • 1