ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer

SIMPLE SUMMARY: Ataxia telangiectasia mutated (ATM) protein plays a pivotal role in the DNA-damage response through activation of many different molecular targets. Mutations of the related gene cause Ataxia Telangiectasia (A-T) disease, characterized by neurodegeneration, immunodeficiency, and predisposition to lymphoid tumors, and they have been also found associated with several malignancies. The clinical heterogeneity of A-T can be attributed to different types of mutations that impair the expression of the protein or have a different impact on its function. In particular, extremely rare mutations that preserve the protein expression but abrogate the activity have been reported to be more dangerous in A-T patients and in mouse models. In cancer patients, these mutations have been correlated both to lymphoid and non-lymphoid tumors. The review summarizes the current knowledge on the so called “Kinase Dead” (KD) mutations of ATM protein that can be used in personalized treatments of A-T or oncologic patients. ABSTRACT: ATM is one of the principal players of the DNA damage response. This protein exerts its role in DNA repair during cell cycle replication, oxidative stress, and DNA damage from endogenous events or exogenous agents. When is activated, ATM phosphorylates multiple substrates that participate in DNA repair, through its phosphoinositide 3-kinase like domain at the 3′end of the protein. The absence of ATM is the cause of a rare autosomal recessive disorder called Ataxia Telangiectasia characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. There is a correlation between the severity of the phenotype and the mutations, depending on the residual activity of the protein. The analysis of patient mutations and mouse models revealed that the presence of inactive ATM, named ATM kinase-dead, is more cancer prone and lethal than its absence. ATM mutations fall into the whole gene sequence, and it is very difficult to predict the resulting effects, except for some frequent mutations. In this regard, is necessary to characterize the mutated protein to assess if it is stable and maintains some residual kinase activity. Moreover, the whole-genome sequencing of cancer patients with somatic or germline mutations has highlighted a high percentage of ATM mutations in the phosphoinositide 3-kinase domain, mostly in cancer cells resistant to classical therapy. The relevant differences between the complete absence of ATM and the presence of the inactive form in in vitro and in vivo models need to be explored in more detail to predict cancer predisposition of A-T patients and to discover new therapies for ATM-associated cancer cells. In this review, we summarize the multiple discoveries from humans and mouse models on ATM mutations, focusing into the inactive versus null ATM.