Autophosphorylation of DNA-Dependent Protein Kinase Regulates DNA End Processing and May Also Alter Double-Strand Break Repair Pathway Choice
- 1 December 2005
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 25 (24), 10842-10852
- https://doi.org/10.1128/mcb.25.24.10842-10852.2005
Abstract
Two highly conserved double-strand break (DSB) repair pathways, homologous recombination (HR) and nonhomologous end joining (NHEJ), function in all eukaryotes. How a cell chooses which pathway to utilize is an area of active research and debate. During NHEJ, the DNA-dependent protein kinase (DNA-PK) functions as a “gatekeeper” regulating DNA end access. Here, we provide evidence that DNA-PK regulates DNA end access via its own autophosphorylation. We demonstrated previously that autophosphorylation within a major cluster of sites likely mediates a conformational change that is critical for DNA end processing. Furthermore, blocking autophosphorylation at these sites inhibits a cell's ability to utilize the other major double-strand break repair pathway, HR. Here, we define a second major cluster of DNA-PK catalytic subunit autophosphorylation sites. Whereas blocking phosphorylation at the first cluster inhibits both end processing and HR, blocking phosphorylation at the second cluster enhances both. We conclude that separate DNA-PK autophosphorylation events may function reciprocally by not only regulating DNA end processing but also affecting DSB repair pathway choice.Keywords
This publication has 37 references indexed in Scilit:
- Biochemical characterization of the ataxia-telangiectasia mutated (ATM) protein from human cellsDNA Repair, 2004
- Binding of the DNA-dependent protein kinase catalytic subunit to Holliday junctionsBiochemical Journal, 2004
- DNA–PKcs function regulated specifically by protein phosphatase 5Proceedings of the National Academy of Sciences of the United States of America, 2004
- The role of DNA dependent protein kinase in synapsis of DNA endsNucleic Acids Research, 2003
- Repair of DNA double strand breaks by non-homologous end joiningBiochimie, 2003
- Interactive competition between homologous recombination and non-homologous end joining.2003
- DNA-PK phosphorylation sites in XRCC4 are not required for survival after radiation or for V(D)J recombinationDNA Repair, 2003
- Autophosphorylation of the Catalytic Subunit of the DNA-Dependent Protein Kinase Is Required for Efficient End Processing during DNA Double-Strand Break RepairMolecular and Cellular Biology, 2003
- Pathways of DNA Double-Strand Break Repair during the Mammalian Cell CycleMolecular and Cellular Biology, 2003
- Threonines 2638/2647 in DNA-PK are essential for cellular resistance to ionizing radiation.2003