Cell cycle dependence of DNA-PK phosphorylation in response to DNAdouble strand breaks
DNA-dependent protein kinase (DNA-PK), consisting of Ku and DNA-PKcs subunits, is the key component of the non-homologous end joining (NHEJ) pathway of DNA double strand breaks (DSBs) repair. Though the kinase activity of DNA-PKcs is essential for NHEJ, thus far, no in vivo substrate has been conclusively identified except for an autophosphorylation site on DNA-PKcs itself (threonine 2609). Here we report the IR-induced autophosphorylation of DNA-PKcs at a novel site,serine 2056, and phosphorylation at this site is required for the repair of DSBs by NHEJ. Interestingly, IR-induced DNA-PKcs autophosphorylation is regulated in a cell cycle-dependent manner with attenuated phosphorylation in the S phase. In contrast, DNA replication-associated DSBs result in DNA-PKcs autophosphorylation and localization to DNA damage sites. These results indicate that, while IR-induced DNA-PKcs phosphorylation is attenuated in S phase, DNA-PKcs is preferentially activated by the physiologically relevant DNA replication-associated DSBs at the sites of DNA synthesis.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Director. Office of Science. Office of Biological andEnvironmental Research, Life Sciences Division; National Institutes ofHealth Grants CA50519 and CA86936 and P01-CA92584, Department of Defense.Breast Cancer Research Program Grants DAMD17-00-1-0146 andDAMD17-03-1-0635; Canadian Institutes of health Research, AlbertaHeritage Foundation for Medical Research
- DOE Contract Number:
- DE-AC02-05CH11231
- OSTI ID:
- 861549
- Report Number(s):
- LBNL-54775; JBCHA3; R&D Project: 862R1A; BnR: 400412000; TRN: US200601%%181
- Journal Information:
- Journal of Biological Chemistry, Vol. 280, Issue 15; Related Information: Journal Publication Date: 04/15/2005; ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- English
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