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)

97 Downloads (Pure)

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

Adgang til dokumentet

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

Citationsformater

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. Artikel 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

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater