ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer

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.

Zebrafish: A Relevant Genetic Model for Human Primary Immunodeficiency (PID) Disorders?

“…In addition, knockdown of the zebrafish arpc1b gene resulted in reduced embryonic T cells and thrombocytes [ 42 ], recapitulating human ARPC1B deficiency [ 74 ]. Ataxia-telangiectasia (A-T) syndrome is a human disorder characterized by neurodegeneration, immune dysregulation, cancer susceptibility and premature aging and results from defects in the ATM gene [ 43 ]. Zebrafish LOF atm mutants exhibited similar phenotypes, with multi-lineage immunodeficiency along with motor disturbances and cancer predisposition [ 75 ].…”

Functions of Breast Cancer Predisposition Genes: Implications for Clinical Management

“…Homozygous or compound heterozygous ATM GPVs cause a rare autosomal recessive disorder called A-T, characterized by progressive cerebellar ataxia, telangiectasia, oculomotor apraxia, immunodeficiency, cancer susceptibility, and radiation sensitivity [118]; therefore, counseling ATM GPV carriers against the risk of autosomal recessive conditions in their offspring is recommended [14].…”

Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway

“…ATM GPV heterozygous carriers have an increased risk for several types of cancers, including breast, ovarian, and pancreatic cancers [ 46 , 68 ]. However, the carriers of biallelic ATM GPVs are affected by ataxia–telangiectasia (AT, OMIM #208900), which is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, cutaneous telangiectasias, increased risk of developing hematologic and solid tumors, and immunodeficiency [ 66 , 68 , 69 ].…”

“…A recent meta-analysis [ 45 ] reported the prevalence of ATM GPVs in patients with EOC to be 0.6767% (26/3842 cases) and showed a significant association between ATM GPVs and EOC (odds ratio (OR) = 1.977, 95% confidence interval (CI) = 1.330–2.939) ( Table 1 ). Another population-based cohort study reported that the prevalence of ATM GPVs was 0.57–0.64% [ 18 , 69 ]. The absolute lifetime risk of EOC estimated by the NCCN clinical practice guidelines in oncology is <3% [ 26 , 46 ].…”