ATM and related protein kinases: safeguarding genome integrity

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Abstract
The DNA-damage response is crucial for cellular life and for avoiding neoplasia. It occurs by rapidly transducing the damage signal to many cellular systems, such as the DNA-repair machinery and the cell-cycle checkpoints. Double-strand breaks (DSBs) in the DNA — deadly DNA lesions — mobilize an intricate signalling network by activating the ATM protein kinase, which, in turn, orchestrates this network by phosphorylating one or more key proteins in each of its branches. Other protein kinases related to ATM carry out similar functions in response to other genotoxic stresses, and some of them collaborate with ATM in the DSB response. ATM deficiency leads to ataxia-telangiectasia (A-T), a genomic instability syndrome, the hallmarks of which — neurodegeneration, immunodeficiency, radiation sensitivity and cancer predisposition — show the intimate connection between maintenance of genome stability, cellular and tissue functioning, and cancer prevention. Certain types of ATM mutations seem to increase cancer predisposition in heterozygous carriers. This adds ATM to the list of genes that have sequence variations with important implications for public health, especially with regards to cancer epidemiology.