Format

Send to

Choose Destination
See comment in PubMed Commons below
DNA Repair (Amst). 2010 Dec 10;9(12):1307-14. doi: 10.1016/j.dnarep.2010.09.019. Epub 2010 Oct 28.

A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation.

Author information

1
Department of Biochemistry, Southern Alberta Cancer Research Institute, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta T2N 4Z6, Canada.

Abstract

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ku heterodimer together form the biologically critical DNA-PK complex that plays key roles in the repair of ionizing radiation-induced DNA double-strand breaks through the non-homologous end-joining (NHEJ) pathway. Despite elegant and informative electron microscopy studies, the mechanism by which DNA-PK co-ordinates the initiation of NHEJ has been enigmatic due to limited structural information. Here, we discuss how the recently described small angle X-ray scattering structures of full-length Ku heterodimer and DNA-PKcs in solution, combined with a breakthrough DNA-PKcs crystal structure, provide significant insights into the early stages of NHEJ. Dynamic structural changes associated with a functionally important cluster of autophosphorylation sites play a significant role in regulating the dissociation of DNA-PKcs from Ku and DNA. These new structural insights have implications for understanding the formation and control of the DNA-PK synaptic complex, DNA-PKcs activation and initiation of NHEJ. More generally, they provide prototypic information for the phosphatidylinositol-3 kinase-like (PIKK) family of serine/threonine protein kinases that includes Ataxia Telangiectasia-Mutated (ATM) and ATM-, Rad3-related (ATR) as well as DNA-PKcs.

PMID:
21030321
PMCID:
PMC3045832
DOI:
10.1016/j.dnarep.2010.09.019
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center