TY - JOUR
T1 - Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability
AU - Galanos, Panagiotis
AU - Pappas, George
AU - Polyzos, Alexander
AU - Kotsinas, Athanassios
AU - Svolaki, Ioanna
AU - Giakoumakis, Nickolaos N.
AU - Glytsou, Christina
AU - Pateras, Ioannis S.
AU - Swain, Umakanta
AU - Souliotis, Vassilis L.
AU - Georgakilas, Alexandros G.
AU - Geacintov, Nicholas
AU - Scorrano, Luca
AU - Lukas, Claudia
AU - Lukas, Jiri
AU - Livneh, Zvi
AU - Lygerou, Zoi
AU - Chowdhury, Dipanjan
AU - Sørensen, Claus Storgaard
AU - Bartek, Jiri
AU - Gorgoulis, Vassilis G.
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/3/16
Y1 - 2018/3/16
N2 - 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.
AB - 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.
KW - Break-induced replication (BIR)
KW - Genomic instability
KW - P21
KW - Rad52
KW - Single nucleotide substitution (SNS)
KW - Single strand annealing (SSA)
KW - Translesion DNA synthesis (TLS)
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U2 - 10.1186/s13059-018-1401-9
DO - 10.1186/s13059-018-1401-9
M3 - Article
C2 - 29548335
AN - SCOPUS:85043983198
SN - 1474-7596
VL - 19
JO - Genome biology
JF - Genome biology
IS - 1
M1 - 37
ER -