Pyranone, Thiopyranone, and Pyridone Inhibitors of Phosphatidylinositol 3-Kinase Related Kinases. Structure−Activity Relationships for DNA-Dependent Protein Kinase Inhibition, and Identification of the First Potent and Selective Inhibitor of the Ataxia Telangiectasia Mutated Kinase

2007 ◽  
Vol 50 (8) ◽  
pp. 1958-1972 ◽  
Author(s):  
Jonathan J. Hollick ◽  
Laurent J. M. Rigoreau ◽  
Celine Cano-Soumillac ◽  
Xiaoling Cockcroft ◽  
Nicola J. Curtin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ataxia Telangiectasia ◽  
Selective Inhibitor ◽  
Phosphatidylinositol 3 Kinase ◽  
Ataxia Telangiectasia Mutated ◽  
Dependent Protein Kinase ◽  
Structure Activity Relationships ◽  
Protein Kinase Inhibition ◽  
Structure Activity ◽  
Dependent Protein

scholarly journals DNA-Dependent Protein Kinase Catalytic Subunit: The Sensor for DNA Double-Strand Breaks Structurally and Functionally Related to Ataxia Telangiectasia Mutated

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1143
Author(s):  
Yoshihisa Matsumoto ◽  
Anie Day D. C. Asa ◽  
Chaity Modak ◽  
Mikio Shimada
Keyword(s):  
Protein Kinase ◽  
Ataxia Telangiectasia ◽  
Catalytic Subunit ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
End Joining ◽  
Dependent Protein Kinase ◽  
Strand Breaks ◽  
Dependent Protein

The DNA-dependent protein kinase (DNA-PK) is composed of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ku70/Ku80 heterodimer. DNA-PK is thought to act as the “sensor” for DNA double-stranded breaks (DSB), which are considered the most deleterious type of DNA damage. In particular, DNA-PKcs and Ku are shown to be essential for DSB repair through nonhomologous end joining (NHEJ). The phenotypes of animals and human individuals with defective DNA-PKcs or Ku functions indicate their essential roles in these developments, especially in neuronal and immune systems. DNA-PKcs are structurally related to Ataxia–telangiectasia mutated (ATM), which is also implicated in the cellular responses to DSBs. DNA-PKcs and ATM constitute the phosphatidylinositol 3-kinase-like kinases (PIKKs) family with several other molecules. Here, we review the accumulated knowledge on the functions of DNA-PKcs, mainly based on the phenotypes of DNA-PKcs-deficient cells in animals and human individuals, and also discuss its relationship with ATM in the maintenance of genomic stability.

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