ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response

• Published in: Molecular cell 2017-06, Vol.66 (6), p.801-817
• Main Authors: Blackford, Andrew N., Jackson, Stephen P.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - chemistry; Ataxia Telangiectasia Mutated Proteins - history; Ataxia Telangiectasia Mutated Proteins - metabolism; Calcium-Binding Proteins - antagonists & inhibitors; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - history; Calcium-Binding Proteins - metabolism; Cell Nucleus - enzymology; DNA Damage; DNA Repair - drug effects; Enzyme Activation; History, 20th Century; History, 21st Century; Humans; Models, Molecular; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Phosphorylation; Protein Conformation; Protein Kinase Inhibitors - therapeutic use; Signal Transduction; Structure-Activity Relationship; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2017.05.015

In vertebrate cells, the DNA damage response is controlled by three related kinases: ATM, ATR, and DNA-PK. It has been 20 years since the cloning of ATR, the last of the three to be identified. During this time, our understanding of how these kinases regulate DNA repair and associated events has grown profoundly, although major questions remain unanswered. Here, we provide a historical perspective of their discovery and discuss their established functions in sensing and responding to genotoxic stress. We also highlight what is known regarding their structural similarities and common mechanisms of regulation, as well as emerging non-canonical roles and how our knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health. In vertebrate cells, the DNA damage response is controlled by three related kinases: ATM, ATR, and DNA-PK. It has been 20 years since the cloning of ATR, the last of the three to be identified. During this time, our understanding of how these kinases regulate DNA repair and associated events has grown profoundly, although major questions remain unanswered. Here, we provide a historical perspective of their discovery and discuss their established functions in sensing and responding to genotoxic stress. We also highlight what is known regarding their structural similarities and common mechanisms of regulation, as well as emerging non-canonical roles and how our knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health.