When DNA is damaged such as due to a lesion, a complex signal transduction pathway is activated which is responsible for recognizing the damage and instigating the cell's response for repair. Compared to the other lesion repair mechanisms, DDR is the highest level of repair and is employed for the most complex lesions. DDR consists of various pathways, the most common of which are the DDR kinase signaling cascades. These are controlled by phosphatidylinositol 3-kinase-related kinases (PIKK), and range from DNA-dependent protein kinase (DNA-PKcs) and ataxia telangiectasia-mutated (ATM) most involved in repairing DSBs to the more versatile Rad3-related (ATR). ATR is crucial to human cell viability, while ATM mutations cause the severe disorder ataxia-telangiectasia leading to neurodegeneration, cancer, and immunodeficiency. These three DDR kinases all recognize damage via protein-protein interactions which localize the kinases to the areas of damage. Next, further protein-protein interactions and posttranslational modifications (PTMs) complete the kinase activation, and a series of phosphorylation events takes place. DDR kinases perform repair regulation at three levels - via PTMs, at the level of chromatin, and at the level of the nucleus.