TY - JOUR
T1 - A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation
AU - Dobbs, Tracey A.
AU - Tainer, John A.
AU - Lees-Miller, Susan P.
N1 - Funding Information:
We thank Michal Hammel for help with SAXS analyses and figures and Alberta Innovates-Health Solutions, the Canadian Institutes for Health Research and National Cancer Institute Structural Cell Biology of DNA Repair Machines grant CA92584 for support.
PY - 2010/12/10
Y1 - 2010/12/10
N2 - 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.
AB - 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.
KW - DNA double strand break repair
KW - DNA-PKcs
KW - Non-homologous end joining
KW - Phosphorylation
KW - SAXS
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U2 - 10.1016/j.dnarep.2010.09.019
DO - 10.1016/j.dnarep.2010.09.019
M3 - Review article
C2 - 21030321
AN - SCOPUS:78649446475
SN - 1568-7864
VL - 9
SP - 1307
EP - 1314
JO - DNA Repair
JF - DNA Repair
IS - 12
ER -