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

Genome Biol. 2018 Mar 16;19(1):37. doi: 10.1186/s13059-018-1401-9.


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.

Keywords: Break-induced replication (BIR); Genomic instability; Rad52; Single nucleotide substitution (SNS); Single strand annealing (SSA); Translesion DNA synthesis (TLS); p21WAF1/Cip1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • DNA / biosynthesis
  • DNA Repair*
  • Genomic Instability*
  • Humans
  • Mutation*
  • Rad52 DNA Repair and Recombination Protein / physiology*
  • Tumor Suppressor Protein p53 / physiology*


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Rad52 DNA Repair and Recombination Protein
  • Tumor Suppressor Protein p53
  • DNA