Abstract
Ataxia–telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.
Highlights
Ataxia–telangiectasia (A-T) was first reported in 1957 as a familial syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, and frequent pulmonary infections [1]
We summarize the molecular biology of Ataxia–telangiectasia mutated (ATM), clinical significance of ATM germline pathogenic variants (PVs) in patients with hereditary cancers, and new therapeutic strategies for ATM-related cancers
In response to changes in the chromatin structure caused by hypotonic stress or chloroquine, ATM is activated by the ATM interactor (ATMIN) (Figure 3a) [56]
Summary
Ataxia–telangiectasia (A-T) was first reported in 1957 as a familial syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, and frequent pulmonary infections [1]. A major breakthrough in understating A-T came with the identification of the gene ataxia–telangiectasia mutated (ATM) in A-T patients [4]. Individuals present with milder symptoms if they possess certain missense, in-frame, or leaky splice-site mutations that allow for the production of residual amounts of functioning ATM protein [3]. The cumulative incidence of cancer in A-T patients has been reported to be 38.2% by 40 years of age. A-T symptoms, the diagnosis of cancer can precede the diagnosis of A-T [7,8] Carriers are those who have one mutated copy of the ATM gene and are generally healthy. Multiple studies have documented associations between increased risk of several types of cancers and heterozygous ATM germline pathogenic variants (PVs) [10,11,12]. We summarize the molecular biology of ATM, clinical significance of ATM germline PVs in patients with hereditary cancers, and new therapeutic strategies for ATM-related cancers
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