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'-OH and dephosphorylates 3'-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 PNKP-Ser 114 and Ser 126-are 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.
authors.affiliation: The David and Inez Myers Laboratory for Cancer Genetics, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Hava
authors.initials: H
authors.lastname: Segal-Raz
authors.forename: Gilad
authors.initials: G
authors.lastname: Mass
authors.forename: Keren
authors.initials: K
authors.lastname: Baranes-Bachar
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Lerenthal
authors.forename: Shih-Ya
authors.initials: SY
authors.lastname: Wang
authors.forename: Young Min
authors.initials: YM
authors.lastname: Chung
authors.forename: Shelly
authors.initials: S
authors.lastname: Ziv-Lehrman
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Ström
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: Mickey C-T
authors.initials: MC
authors.lastname: Hu
authors.forename: David J
authors.initials: DJ
authors.lastname: Chen
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shiloh
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003603:Cytotoxins / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000502:physiology*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D009353:Zinostatin / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D003603:Cytotoxins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D009353:Zinostatin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D045643:DNA Repair Enzymes