DNA-PK is activated by nucleosomes and phosphorylates H2AX within the nucleosomes in an acetylation-dependent manner

Eun Jung Park, Doug W. Chan, Ji Hye Park, Marjorie A. Oettinger, Jongbum Kwon

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124 Scopus citations


Eukaryotic DNA is organized into nucleosomes and higher order chromatin structure, which plays an important role in the regulation of many nuclear processes including DNA repair. Non-homologous end-joining, the major pathway for repairing DNA double-strand breaks (DSBs) in mammalian cells, is mediated by a set of proteins including DNA-dependent protein kinase (DNA-PK). DNA-PK is comprised of a large catalytic subunit, DNA-PKcs, and its regulatory subunit, Ku. Current models predict that Ku binds to the ends of broken DNA and DNA-PKcs is recruited to form the active kinase complex. Here we show that DNA-PK can be activated by nucleosomes through the ability of Ku to bind to the ends of nucleosomal DNA, and that the activated DNA-PK is capable of phosphorylating H2AX within the nucleosomes. Histone acetylation has little effect on the steps of Ku binding to nucleosomes and subsequent activation of DNA-PKcs. However, acetylation largely enhances the phosphorylation of H2AX by DNA-PK, and this acetylation effect is observed when H2AX exists in the context of nucleosomes but not in a free form. These results suggest that the phosphorylation of H2AX, known to be important for DSB repair, can be regulated by acetylation and may provide a mechanistic basis on which to understand the recent observations that histone acetylation critically functions in repairing DNA DSBs.

Original languageEnglish
Pages (from-to)6819-6827
Number of pages9
JournalNucleic Acids Research
Issue number23
StatePublished - 1 Dec 2003

Bibliographical note

Funding Information:
D.W.C was supported by postdoctoral fellowships from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research. M.A.O. was supported by the Leukemia and Lymphoma Scholars Program. This work was supported by the Brain Korea 21 Project (J.K.).


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