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 journalArticle

41 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 languageEnglish (US)
Pages (from-to)713-719
Number of pages7
JournalEMBO Reports
Volume12
Issue number7
DOIs
StatePublished - 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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    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