ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair

Hava Segal-Raz; Gilad Mass; Keren Baranes-Bachar; Yaniv Lerenthal; Shih Ya Wang; Young Min Chung; Shelly Ziv-Lehrman; Cecilia E. Ström; Thomas Helleday; Mickey C T Hu; David J. Chen; Yosef Shiloh

doi:10.1038/embor.2011.96

ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair

Hava Segal-Raz, Gilad Mass, Keren Baranes-Bachar, Yaniv Lerenthal, Shih Ya Wang, Young Min Chung, Shelly Ziv-Lehrman, Cecilia E. Ström, Thomas Helleday, Mickey C T Hu, David J. Chen, Yosef Shiloh

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

The cellular response to double-strand breaks (DSBs) in DNA is a complex signalling network, mobilized by the nuclear protein kinase ataxia- telangiectasia mutated (ATM), which phosphorylates many factors in the various branches of this network. A main question is how ATM regulates DSB repair. Here, we identify the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) as an ATM target. PNKP phosphorylates 5-2-OH and dephosphorylates 3-2-phosphate DNA ends that are formed at DSB termini caused by DNA-damaging agents, thereby regenerating legitimate ends for further processing. We establish that the ATM phosphorylation targets on human PNKPSer 114 and Ser 126are crucial for cellular survival following DSB induction and for effective DSB repair, being essential for damage-induced enhancement of the activity of PNKP and its proper accumulation at the sites of DNA damage. These findings show a direct functional link between ATM and the DSB-repair machinery.

Original language	English (US)
Pages (from-to)	713-719
Number of pages	7
Journal	EMBO Reports
Volume	12
Issue number	7
DOIs	https://doi.org/10.1038/embor.2011.96
State	Published - Jul 2011

Keywords

ATM
DNA damage response
double strand break repair
polynucleotide kinase/phosphatase
protein phosphorylation

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics

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10.1038/embor.2011.96

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Segal-Raz, H., Mass, G., Baranes-Bachar, K., Lerenthal, Y., Wang, S. Y., Chung, Y. M., Ziv-Lehrman, S., Ström, C. E., Helleday, T., Hu, M. C. T., Chen, D. J., & Shiloh, Y. (2011). ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair. EMBO Reports, 12(7), 713-719. https://doi.org/10.1038/embor.2011.96

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title = "ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair",

abstract = "The cellular response to double-strand breaks (DSBs) in DNA is a complex signalling network, mobilized by the nuclear protein kinase ataxia- telangiectasia mutated (ATM), which phosphorylates many factors in the various branches of this network. A main question is how ATM regulates DSB repair. Here, we identify the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) as an ATM target. PNKP phosphorylates 5-2-OH and dephosphorylates 3-2-phosphate DNA ends that are formed at DSB termini caused by DNA-damaging agents, thereby regenerating legitimate ends for further processing. We establish that the ATM phosphorylation targets on human PNKPSer 114 and Ser 126are crucial for cellular survival following DSB induction and for effective DSB repair, being essential for damage-induced enhancement of the activity of PNKP and its proper accumulation at the sites of DNA damage. These findings show a direct functional link between ATM and the DSB-repair machinery.",

keywords = "ATM, DNA damage response, double strand break repair, polynucleotide kinase/phosphatase, protein phosphorylation",

author = "Hava Segal-Raz and Gilad Mass and Keren Baranes-Bachar and Yaniv Lerenthal and Wang, {Shih Ya} and Chung, {Young Min} and Shelly Ziv-Lehrman and Str{\"o}m, {Cecilia E.} and Thomas Helleday and Hu, {Mickey C T} and Chen, {David J.} and Yosef Shiloh",

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doi = "10.1038/embor.2011.96",

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AU - Mass, Gilad

AU - Baranes-Bachar, Keren

AU - Lerenthal, Yaniv

AU - Wang, Shih Ya

AU - Chung, Young Min

AU - Ziv-Lehrman, Shelly

AU - Ström, Cecilia E.

AU - Helleday, Thomas

AU - Hu, Mickey C T

AU - Chen, David J.

AU - Shiloh, Yosef

PY - 2011/7

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N2 - The cellular response to double-strand breaks (DSBs) in DNA is a complex signalling network, mobilized by the nuclear protein kinase ataxia- telangiectasia mutated (ATM), which phosphorylates many factors in the various branches of this network. A main question is how ATM regulates DSB repair. Here, we identify the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) as an ATM target. PNKP phosphorylates 5-2-OH and dephosphorylates 3-2-phosphate DNA ends that are formed at DSB termini caused by DNA-damaging agents, thereby regenerating legitimate ends for further processing. We establish that the ATM phosphorylation targets on human PNKPSer 114 and Ser 126are crucial for cellular survival following DSB induction and for effective DSB repair, being essential for damage-induced enhancement of the activity of PNKP and its proper accumulation at the sites of DNA damage. These findings show a direct functional link between ATM and the DSB-repair machinery.

AB - The cellular response to double-strand breaks (DSBs) in DNA is a complex signalling network, mobilized by the nuclear protein kinase ataxia- telangiectasia mutated (ATM), which phosphorylates many factors in the various branches of this network. A main question is how ATM regulates DSB repair. Here, we identify the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) as an ATM target. PNKP phosphorylates 5-2-OH and dephosphorylates 3-2-phosphate DNA ends that are formed at DSB termini caused by DNA-damaging agents, thereby regenerating legitimate ends for further processing. We establish that the ATM phosphorylation targets on human PNKPSer 114 and Ser 126are crucial for cellular survival following DSB induction and for effective DSB repair, being essential for damage-induced enhancement of the activity of PNKP and its proper accumulation at the sites of DNA damage. These findings show a direct functional link between ATM and the DSB-repair machinery.

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ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair

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