Περίληψη:
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. © 2018 The Author(s).
Συγγραφείς:
Galanos, P.
Pappas, G.
Polyzos, A.
Kotsinas, A.
Svolaki, I.
Giakoumakis, N.N.
Glytsou, C.
Pateras, I.S.
Swain, U.
Souliotis, V.L.
Georgakilas, A.G.
Geacintov, N.
Scorrano, L.
Lukas, C.
Lukas, J.
Livneh, Z.
Lygerou, Z.
Chowdhury, D.
Sørensen, C.S.
Bartek, J.
Gorgoulis, V.G.
Λέξεις-κλειδιά:
cyclin dependent kinase inhibitor 1; nucleotide; protein p21; protein p53; Rad52 protein; transcription factor E2F1; CDKN1A protein, human; cyclin dependent kinase inhibitor 1A; DNA; protein p53; Rad52 protein, Article; break induced replication; controlled study; DNA repair; DNA replication; DNA synthesis; DNA transcription; double stranded DNA break; enzyme activation; gene control; gene expression; genetic load; genomic instability; human; human cell; human experiment; mutational analysis; nucleic acid base substitution; protein expression; single nucleotide polymorphism; single strand annealing repair; synthesis dependent strand annealing repair; tumor suppressor gene; biosynthesis; cell line; DNA repair; metabolism; mutation; physiology, Cell Line; Cyclin-Dependent Kinase Inhibitor p21; DNA; DNA Repair; Genomic Instability; Humans; Mutation; Rad52 DNA Repair and Recombination Protein; Tumor Suppressor Protein p53
