TY - JOUR
TI - Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability
AU - Galanos, P.
AU - Pappas, G.
AU - Polyzos, A.
AU - Kotsinas, A.
AU - Svolaki, I.
AU - Giakoumakis, N.N.
AU - Glytsou, C.
AU - Pateras, I.S.
AU - Swain, U.
AU - Souliotis, V.L.
AU - Georgakilas, A.G.
AU - Geacintov, N.
AU - Scorrano, L.
AU - Lukas, C.
AU - Lukas, J.
AU - Livneh, Z.
AU - Lygerou, Z.
AU - Chowdhury, D.
AU - Sørensen, C.S.
AU - Bartek, J.
AU - Gorgoulis, V.G.
JO - Genome Biology
PY - 2018
VL - 19
TODO - 1
SP - null
PB - BioMed Central Ltd.
SN - 1465-6906, 1474-760X
TODO - 10.1186/s13059-018-1401-9
TODO - 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
TODO - 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).
ER -