Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks

Sotirios K Sotiriou; Irene Kamileri; Natalia Lugli; Konstantinos Evangelou; Caterina Da-Ré; Florian Huber; Laura Padayachy; Sebastien Tardy; Noemie L Nicati; Samia Barriot; Fena Ochs; Claudia Lukas; Jiri Lukas; Vassilis G Gorgoulis; Leonardo Scapozza; Thanos D Halazonetis

doi:10.1016/j.molcel.2016.10.038

Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks

Sotirios K Sotiriou, Irene Kamileri, Natalia Lugli, Konstantinos Evangelou, Caterina Da-Ré, Florian Huber, Laura Padayachy, Sebastien Tardy, Noemie L Nicati, Samia Barriot, Fena Ochs, Claudia Lukas, Jiri Lukas, Vassilis G Gorgoulis, Leonardo Scapozza, Thanos D Halazonetis

129 Citationer (Scopus)

Abstract

Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells.

Originalsprog	Engelsk
Tidsskrift	Molecular Cell
Vol/bind	64
Udgave nummer	6
Sider (fra-til)	1127-1134
Antal sider	8
ISSN	1097-2765
DOI	https://doi.org/10.1016/j.molcel.2016.10.038
Status	Udgivet - 15 dec. 2016

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10.1016/j.molcel.2016.10.038Licens: CC BY-NC-ND

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Sotiriou, S. K., Kamileri, I., Lugli, N., Evangelou, K., Da-Ré, C., Huber, F., Padayachy, L., Tardy, S., Nicati, N. L., Barriot, S., Ochs, F., Lukas, C., Lukas, J., Gorgoulis, V. G., Scapozza, L., & Halazonetis, T. D. (2016). Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks. Molecular Cell, 64(6), 1127-1134. https://doi.org/10.1016/j.molcel.2016.10.038

Sotiriou, SK, Kamileri, I, Lugli, N, Evangelou, K, Da-Ré, C, Huber, F, Padayachy, L, Tardy, S, Nicati, NL, Barriot, S, Ochs, F, Lukas, C , Lukas, J, Gorgoulis, VG, Scapozza, L & Halazonetis, TD 2016, 'Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks', Molecular Cell, bind 64, nr. 6, s. 1127-1134. https://doi.org/10.1016/j.molcel.2016.10.038

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title = "Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks",

abstract = "Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells.",

author = "Sotiriou, {Sotirios K} and Irene Kamileri and Natalia Lugli and Konstantinos Evangelou and Caterina Da-R{\'e} and Florian Huber and Laura Padayachy and Sebastien Tardy and Nicati, {Noemie L} and Samia Barriot and Fena Ochs and Claudia Lukas and Jiri Lukas and Gorgoulis, {Vassilis G} and Leonardo Scapozza and Halazonetis, {Thanos D}",

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doi = "10.1016/j.molcel.2016.10.038",

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T1 - Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks

AU - Sotiriou, Sotirios K

AU - Kamileri, Irene

AU - Lugli, Natalia

AU - Evangelou, Konstantinos

AU - Da-Ré, Caterina

AU - Huber, Florian

AU - Padayachy, Laura

AU - Tardy, Sebastien

AU - Nicati, Noemie L

AU - Barriot, Samia

AU - Ochs, Fena

AU - Lukas, Claudia

AU - Lukas, Jiri

AU - Gorgoulis, Vassilis G

AU - Scapozza, Leonardo

AU - Halazonetis, Thanos D

PY - 2016/12/15

Y1 - 2016/12/15

N2 - Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells.

AB - Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells.

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DO - 10.1016/j.molcel.2016.10.038

M3 - Journal article

C2 - 27984746

SN - 1097-2765

VL - 64

SP - 1127

EP - 1134

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks

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