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[Cancer Research 63, 1198-1201, March 15, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

Threonines 2638/2647 in DNA-PK Are Essential for Cellular Resistance to Ionizing Radiation1

Sébastien Soubeyrand, Louise Pope, Benjamin Pakuts and Robert J. G. Haché2

Departments of Medicine [S. S., L. P., B. P., R. J. G. H.] and Biochemistry, Microbiology, and Immunology [R. J. G. H.], University of Ottawa, the Ottawa Health Research Institute, Ottawa, Ontario, K1Y 4E9 Canada

DNA-dependent protein kinase (DNA-PK) is required for the repair of double-strandedDNA breaks through the nonhomologous DNA end joining pathway. DNA-PK activity is required for DNA repair, but kinase activity also appears to be attenuated through an autoregulatory feedback loop. We show that autophosphorylation of DNA-PK catalytic subunit occurs in trans at least three sites NH2 terminal to the catalytic domain and that two sites, threonine 2638 and 2647, determine DNA-PK autophosphorylation in vitro. Thr2638/2647ala substitution in DNA-PK catalytic subunit compromised cellular resistance to ionizing radiation without affecting DNA end joining, suggesting a requirement for DNA-PK inactivation for cell survival at a step after the rejoining of double-stranded DNA breaks.




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