Article
- The EMBO Journal (2004) 23, 3874 - 3885
- doi:10.1038/sj.emboj.7600375
Published online: 23 September 2004
Subject Category:
Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV
Christine Anne Koch1,2,3, Roger Agyei1, Sarah Galicia1, Pavel Metalnikov1, Paul O'Donnell1, Andrei Starostine1, Michael Weinfeld4 and Daniel Durocher1,5
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Radiation Medicine Program, Princess Margaret Hospital (UHN), Toronto, ON, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Cross Cancer Institute, Edmonton, Alberta, Canada
- Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Canada
Correspondence to:
Daniel Durocher, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Room 1073, 600 University Avenue, Toronto, Canada ON M5G 1X5. Tel.: +1 416 586 4800 x2544; Fax: +1 416 586 8869; E-mail: durocher@mshri.on.ca
Christine Anne Koch, Radiation Medicine Program, Princess Margaret Hospital (UHN), 610 University Avenue, 5th floor Toronto, Canada ON M5G 2M9
Received 3 March 2004; Accepted 27 July 2004
Abstract
Nonhomologous end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammalian cells. A critical step in this process is DNA ligation, involving the Xrcc4–DNA ligase IV complex. DNA end processing is often a prerequisite for ligation, but the coordination of these events is poorly understood. We show that polynucleotide kinase (PNK), with its ability to process ionizing radiation-induced 5'-OH and 3'-phosphate DNA termini, functions in NHEJ via an FHA-dependent interaction with CK2-phosphorylated Xrcc4. Analysis of the PNK FHA–Xrcc4 interaction revealed that the PNK FHA domain binds phosphopeptides with a unique selectivity among FHA domains. Disruption of the Xrcc4–PNK interaction in vivo is associated with increased radiosensitivity and slower repair kinetics of DSBs, in conjunction with a diminished efficiency of DNA end joining in vitro. Therefore, these results suggest a new role for Xrcc4 in the coordination of DNA end processing with DNA ligation.
Keywords:
- DNA double-strand breaks,
- DNA repair,
- FHA domain,
- nonhomologous end joining,
- Xrcc4
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