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PMID:18710952

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Citation

Ruis, BL, Fattah, KR and Hendrickson, EA (2008) The catalytic subunit of DNA-dependent protein kinase regulates proliferation, telomere length, and genomic stability in human somatic cells. Mol. Cell. Biol. 28:6182-95

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 nonhomologous end-joining 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 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 missing due to the lack of patients with mutations in any one of the three DNA-PK subunits. The worldwide 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 for other mammalian systems.

Links

PubMed PMC2577426 Online version:10.1128/MCB.00355-08

Keywords

Biomarkers/metabolism; Catalytic Domain; Cell Cycle/drug effects; Cell Proliferation/drug effects; DNA Damage; DNA-Activated Protein Kinase/deficiency; DNA-Activated Protein Kinase/metabolism; Etoposide/pharmacology; Gene Targeting; Genomic Instability/drug effects; HCT116 Cells; Heterozygote; Homozygote; Humans; Telomere/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:XRCC6

involved_in

GO:0000723: telomere maintenance

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:XRCC5

involved_in

GO:0032204: regulation of telomere maintenance

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKDC

involved_in

GO:0050678: regulation of epithelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0011108)

Seeded From UniProt

complete

HUMAN:PRKDC

involved_in

GO:0016233: telomere capping

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKDC

involved_in

GO:0050678: regulation of epithelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0011108)

Seeded From UniProt

complete

HUMAN:PRKDC

involved_in

GO:0006302: double-strand break repair

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKDC

involved_in

GO:0097681: double-strand break repair via alternative nonhomologous end joining

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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