Journal
GENES & DEVELOPMENT
Volume 16, Issue 18, Pages 2333-2338Publisher
COLD SPRING HARBOR LAB PRESS
DOI: 10.1101/gad.1015202
Keywords
nonhomologous end-joining; DNA damage response; autophosphorylation; DNA-PK; DNA-PKcs; Ku; radiation sensitivity; ionizing radiation
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Funding
- NCI NIH HHS [R01 CA050519, CA50519, R37 CA050519, P01 CA092584, CA92584] Funding Source: Medline
- NIA NIH HHS [AG917709] Funding Source: Medline
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Nonhomologous end-joining (NHEJ) is the predominant pathway that repairs DNA double-strand breaks (DSBs) in mammalian cells. The DNA-dependent protein kinase (DNA-PK), consisting of Ku and DNA-PK catalytic subunit (DNA-PKcs), is activated by DNA in vitro and is required for NHEJ. We report that DNA-PKcs is auto-phosphorylated at Thr2609 in vivo in a Ku-dependent manner in response to ionizing radiation. Phosphorylated DNA-PKcs colocalizes with both gamma-H2AX and 53BP1 after DNA damage. Mutation of Thr2609 to Ala leads to radiation sensitivity and impaired DSB rejoining. These findings establish that Ku-dependent phosphorylation of DNA-PKcs at Thr2609 is required for the repair of DSBs by NHEJ.
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