Differential role of DNA-PKcs phosphorylations and kinase activity in radiosensitivity and chromosomal instability

Hatsumi Nagasawa, John B. Little, Yu Fen Lin, Sairei So, Akihiro Kurimasa, Yuanlin Peng, John R. Brogan, David J. Chen, Joel S. Bedford, Benjamin P C Chen

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is the key functional element in the DNA-PK complex that drives nonhomologous end joining (NHEJ), the predominant DNA double-strand break (DSB) repair mechanism operating to rejoin such breaks in mammalian cells after exposure to ionizing radiation. It has been reported that DNA-PKcs phosphorylation and kinase activity are critical determinants of radiosensitivity, based on responses reported after irradiation of asynchronously dividing populations of various mutant cell lines. In the present study, the relative radiosensitivity to cell killing as well as chromosomal instability of 13 DNA-PKcs site-directed mutant cell lines (defective at phosphorylation sites or kinase activity) were examined after exposure of synchronized G1 cells to 137Cs γ rays. DNA-PKcs mutant cells defective in phosphorylation at multiple sites within the T2609 cluster or within the PI3K domain displayed extreme radiosensitivity. Cells defective at the S2056 cluster or T2609 single site alone were only mildly radiosensitive, but cells defective at even one site in both the S2056 and T2609 clusters were maximally radiosensitive. Thus a synergism between the capacity for phosphorylation at the S2056 and T2609 clusters was found to be critical for induction of radiosensitivity.

Original languageEnglish (US)
Pages (from-to)83-89
Number of pages7
JournalRadiation research
Volume175
Issue number1
DOIs
StatePublished - Jan 2011

ASJC Scopus subject areas

  • Biophysics
  • Radiation
  • Radiology Nuclear Medicine and imaging

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    Nagasawa, H., Little, J. B., Lin, Y. F., So, S., Kurimasa, A., Peng, Y., Brogan, J. R., Chen, D. J., Bedford, J. S., & Chen, B. P. C. (2011). Differential role of DNA-PKcs phosphorylations and kinase activity in radiosensitivity and chromosomal instability. Radiation research, 175(1), 83-89. https://doi.org/10.1667/RR2092.1