A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation
| Autor: | Tracey A. Dobbs, John A. Tainer, Susan P. Lees-Miller |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular DNA Repair DNA repair Protein subunit DNA-Activated Protein Kinase Biology Biochemistry DNA-binding protein Article DNA Breaks Double-Stranded Phosphorylation Protein kinase A Molecular Biology Ku Autoantigen DNA-PKcs Autophosphorylation DNA Helicases Nuclear Proteins Cell Biology DNA repair protein XRCC4 Cell biology Non-homologous end joining DNA-Binding Proteins enzymes and coenzymes (carbohydrates) biological phenomena cell phenomena and immunity |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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