Galanos, PanagiotisPappas, GeorgePolyzos, AlexanderKotsinas, AthanassiosSvolaki, IoannaGiakoumakis, Nickolaos N.Glytsou, ChristinaPateras, Ioannis S.Swain, UmakantaSouliotis, Vassilis L.Georgakilas, Alexandros G.Geacintov, NicholasScorrano, LucaLukas, ClaudiaLukas, JiriLivneh, ZviLygerou, ZoiChowdhury, DipanjanSørensen, Claus StorgaardBartek, JiriGorgoulis, Vassilis G.2018-04-192018Galanos, P., G. Pappas, A. Polyzos, A. Kotsinas, I. Svolaki, N. N. Giakoumakis, C. Glytsou, et al. 2018. “Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability.” Genome Biology 19 (1): 37. doi:10.1186/s13059-018-1401-9. http://dx.doi.org/10.1186/s13059-018-1401-9.http://nrs.harvard.edu/urn-3:HUL.InstRepos:35982016Background: 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. Electronic supplementary material The online version of this article (10.1186/s13059-018-1401-9) contains supplementary material, which is available to authorized users.en-USp21Rad52Genomic instabilityTranslesion DNA synthesis (TLS)Single nucleotide substitution (SNS)Break-induced replication (BIR)Single strand annealing (SSA)Journal Article2018-04-1910.1186/s13059-018-1401-9