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

Panagiotis Galanos; George Pappas; Alexander Polyzos; Athanassios Kotsinas; Ioanna Svolaki; Nickolaos N Giakoumakis; Christina Glytsou; Ioannis S Pateras; Umakanta Swain; Vassilis L Souliotis; Alexandros G Georgakilas; Nicholas Geacintov; Luca Scorrano; Claudia Lukas; Jiri Lukas; Zvi Livneh; Zoi Lygerou; Dipanjan Chowdhury; Claus Storgaard Sørensen; Jiri Bartek; Vassilis G Gorgoulis

doi:10.1186/s13059-018-1401-9

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

Panagiotis Galanos, George Pappas, Alexander Polyzos, Athanassios Kotsinas, Ioanna Svolaki, Nickolaos N Giakoumakis, Christina Glytsou, Ioannis S Pateras, Umakanta Swain, Vassilis L Souliotis, Alexandros G Georgakilas, Nicholas Geacintov, Luca Scorrano, Claudia Lukas, Jiri Lukas, Zvi Livneh, Zoi Lygerou, Dipanjan Chowdhury, Claus Storgaard Sørensen, Jiri BartekVassilis G Gorgoulis

28 Citationer (Scopus)

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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/Cip1can 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/Cip1expression rewires the repair process and identifies Rad52 as a source of genomic instability and a candidate therapeutic target.

Originalsprog	Engelsk
Artikelnummer	37
Tidsskrift	Genome Biology (Online Edition)
Vol/bind	19
Sider (fra-til)	1-18
ISSN	1474-7596
DOI	https://doi.org/10.1186/s13059-018-1401-9
Status	Udgivet - 2018

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10.1186/s13059-018-1401-9

Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instabilityForlagets udgivne version, 5,29 MB

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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., ... Gorgoulis, V. G. (2018). Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability. Genome Biology (Online Edition), 19, 1-18. [37]. https://doi.org/10.1186/s13059-018-1401-9

Galanos, P, Pappas, G, Polyzos, A, Kotsinas, A, Svolaki, I, Giakoumakis, NN, Glytsou, C, Pateras, IS, Swain, U, Souliotis, VL, Georgakilas, AG, Geacintov, N, Scorrano, L, Lukas, C , Lukas, J, Livneh, Z, Lygerou, Z, Chowdhury, D, Sørensen, CS, Bartek, J & Gorgoulis, VG 2018, 'Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability', Genome Biology (Online Edition), bind 19, 37, s. 1-18. https://doi.org/10.1186/s13059-018-1401-9

@article{1cc7316ac6c349e39092c7229129e2bf,

title = "Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability",

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/Cip1can 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/Cip1expression rewires the repair process and identifies Rad52 as a source of genomic instability and a candidate therapeutic target.",

keywords = "Break-induced replication (BIR), Genomic instability, P21, Rad52, Single nucleotide substitution (SNS), Single strand annealing (SSA), Translesion DNA synthesis (TLS)",

author = "Panagiotis Galanos and George Pappas and Alexander Polyzos and Athanassios Kotsinas and Ioanna Svolaki and Giakoumakis, {Nickolaos N} and Christina Glytsou and Pateras, {Ioannis S} and Umakanta Swain and Souliotis, {Vassilis L} and Georgakilas, {Alexandros G} and Nicholas Geacintov and Luca Scorrano and Claudia Lukas and Jiri Lukas and Zvi Livneh and Zoi Lygerou and Dipanjan Chowdhury and S{\o}rensen, {Claus Storgaard} and Jiri Bartek and Gorgoulis, {Vassilis G}",

year = "2018",

doi = "10.1186/s13059-018-1401-9",

language = "English",

volume = "19",

pages = "1--18",

journal = "Genome Biology (Online Edition)",

issn = "1474-7596",

publisher = "BioMed Central Ltd.",

}

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

PY - 2018

Y1 - 2018

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/Cip1can 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/Cip1expression 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/Cip1can 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/Cip1expression 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)

U2 - 10.1186/s13059-018-1401-9

DO - 10.1186/s13059-018-1401-9

M3 - Journal article

C2 - 29548335

SN - 1474-7596

VL - 19

SP - 1

EP - 18

JO - Genome Biology (Online Edition)

JF - Genome Biology (Online Edition)

M1 - 37

ER -

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

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