Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability
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- Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability
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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.
|Journal||Genome Biology (Online Edition)|
|Publication status||Published - 2018|
- Break-induced replication (BIR), Genomic instability, P21, Rad52, Single nucleotide substitution (SNS), Single strand annealing (SSA), Translesion DNA synthesis (TLS)
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