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

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

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/Cip1can 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/Cip1expression rewires the repair process and identifies Rad52 as a source of genomic instability and a candidate therapeutic target.

OriginalsprogEngelsk
Artikelnummer37
TidsskriftGenome Biology (Online Edition)
Vol/bind19
Sider (fra-til)1-18
ISSN1474-7596
DOI
StatusUdgivet - 2018

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