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Mol. Cell. Biol. doi:10.1128/MCB.00355-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

DNA-PK_cs Regulates Proliferation, Telomere Length and Genomic Stability in Human Somatic Cells

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455

^* To whom correspondence should be addressed. Email: hendr064{at}umn.edu.

	Abstract

The DNA-dependent protein kinase (DNA-PK) complex is a serine/threonine protein kinase comprised of a 469-kDa catalytic subunit (DNA-PK_cs) and the DNA binding regulatory heterodimeric (Ku70/Ku86) complex, Ku. DNA-PK functions in the non-homologous end-joining (NHEJ) pathway for the repair of DNA double-stranded breaks (DSBs) introduced by either exogenous DNA damage or endogenous processes, such as lymphoid V(D)J recombination. Not surprisingly, mutations in either Ku70, Ku86 or DNA-PK_cs result in animals that are sensitive to agents that cause DSBs and that are also immune deficient. While these phenotypes have been validated in several model systems, an extension of them to humans has been lacking due to the lack of patients with mutations in any one of the three DNA-PK subunits. The world-wide lack of patients suggests that during mammalian evolution this complex has become uniquely essential in primates. This hypothesis was substantiated by the demonstration that functional inactivation of either Ku70 or Ku86 in human somatic cell lines is lethal. Here we report on the functional inactivation of DNA-PK_cs in human somatic cells. Surprisingly, DNA-PK_cs does not appear to be essential, although the cell line lacking this gene has profound proliferation and genomic stability deficits not observed in other mammalian systems.