DNA-PKcs function regulated specifically by protein phosphatase 5.
Unrepaired DNA double-strand breaks can lead to apoptosis or tumorigenesis. In mammals double-strand breaks are repaired mainly by nonhomologous end-joining mediated by the DNA-PK complex. The core protein of this complex, DNA-PKcs, is a DNA-dependent serine/threonine kinase that phosphorylates protein targets as well as itself. Although the (auto)phosphorylation activity has been shown to be essential for repair of both random double-strand breaks and induced breaks at the immunoglobulin locus, the corresponding phosphatase has been elusive. In fact, to date, none of the putative phosphatases in DNA double-strand break repair has been identified. Here we show that protein phosphatase 5 interacts with DNA-PKcs and dephosphorylates with surprising specificity at least two functional sites. Cells with either hypo- or hyperphosphorylation of DNA-PKcs at these sites show increased radiation sensitivity.
Wechsler
Thomas
T
Department of Microbiology and Immunology and UCSF Cancer Center, University of California, San Francisco, CA 94143, USA.
Chen
Benjamin P C
BP
Harper
Ryan
R
Morotomi-Yano
Keiko
K
Huang
Betty C B
BC
Meek
Katheryn
K
Cleaver
James E
JE
Chen
David J
DJ
Wabl
Matthias
M
D000818:Animals; D016466:CHO Cells; D020134:Catalytic Domain; D006224:Cricetinae; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011836:Radiation Tolerance
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5