@article{3058571,
    title = "Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability",
    author = "Galanos, P. and Pappas, G. and Polyzos, A. and Kotsinas, A. and Svolaki, I. and Giakoumakis, N.N. and Glytsou, C. and Pateras, I.S. and Swain, U. and Souliotis, V.L. and Georgakilas, A.G. and Geacintov, N. and Scorrano, L. and Lukas, C. and Lukas, J. and Livneh, Z. and Lygerou, Z. and Chowdhury, D. and Sørensen, C.S. and Bartek, J. and Gorgoulis, V.G.",
    journal = "Genome Biology",
    year = "2018",
    volume = "19",
    number = "1",
    publisher = "BioMed Central Ltd.",
    issn = "1465-6906, 1474-760X",
    doi = "10.1186/s13059-018-1401-9",
    keywords = "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",
    abstract = "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)."
}