Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

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 p21 WAF1/Cip1 , showing that its chronic expression...

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Vydáno v:Genome Biology Ročník 19; číslo 1; s. 37
Hlavní autoři: Galanos, Panagiotis, Pappas, George, Polyzos, Alexander, Kotsinas, Athanassios, Svolaki, Ioanna, Giakoumakis, Nickolaos N., Glytsou, Christina, Pateras, Ioannis S., Swain, Umakanta, Souliotis, Vassilis L., Georgakilas, Alexandros G., Geacintov, Nicholas, Scorrano, Luca, Lukas, Claudia, Lukas, Jiri, Livneh, Zvi, Lygerou, Zoi, Chowdhury, Dipanjan, Sørensen, Claus Storgaard, Bartek, Jiri, Gorgoulis, Vassilis G.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London BioMed Central 16.03.2018
Springer Nature B.V
BMC
Témata:
Animal Genetics and Genomics
Bioinformatics
Biomedical and Life Sciences
Break-induced replication (BIR)
Cancer
Cell Line
Cyclin-dependent kinase inhibitor p21
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Deoxyribonucleic acid
DNA
DNA - biosynthesis
DNA damage
DNA Repair
evolution
Evolutionary Biology
Experiments
fuels
genetic instability
genome
Genomes
Genomic Instability
Human Genetics
Humans
Irritable bowel syndrome
landscapes
Life Sciences
Microbial Genetics and Genomics
Mutation
p21WAF1/Cip1
p53 Protein
Plant Genetics and Genomics
Post-translation
Rad52
Rad52 DNA Repair and Recombination Protein - physiology
Rad52 protein
Recruitment
Replication
Senescence
Signatures
Single nucleotide substitution (SNS)
Therapeutic applications
therapeutics
Transcription
transcription (genetics)
Translesion DNA synthesis (TLS)
Tumor Suppressor Protein p53 - physiology
Tumors
Single nucleotide substitution (SNS)
Rad52
Single strand annealing (SSA)
Translesion DNA synthesis (TLS)
Break-induced replication (BIR)
p21
Genomic instability
p21WAF1/Cip1
ISSN:1474-760X, 1474-7596, 1474-760X
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Shrnutí: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 p21 WAF1/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 p21 WAF1/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 p21 WAF1/Cip1 expression rewires the repair process and identifies Rad52 as a source of genomic instability and a candidate therapeutic target.
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ISSN:1474-760X
1474-7596
1474-760X
DOI:10.1186/s13059-018-1401-9