ATM in breast and brain tumors: a comprehensive review

Abstract

The ATM gene is mutated in the syndrome, ataxia-telangiectasia (AT), which is characterized by predisposition to cancer. Patients with AT have an elevated risk of breast and brain tumors Carrying mutations in ATM, patients with AT have an elevated risk of breast and brain tumors. An increased frequency of ATM mutations has also been reported in patients with breast and brain tumors; however, the magnitude of this risk remains uncertain. With the exception of a few common mutations, the spectrum of ATM alterations is heterogeneous in diverse populations, and appears to be remarkably dependent on the ethnicity of patients. This review aims to provide an easily accessible summary of common variants in different populations which could be useful in ATM screening programs. In addition, we have summarized previous research on ATM, including its molecular functions. We attempt to demonstrate the significance of ATM in exploration of breast and brain tumors and its potential as a therapeutic target.

Keywords: Breast cancer; DNA damage; DNA repair; brain tumor.

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ATM plays multiple roles in human cell biology. To be highly active, ATM disunites to monomers; like other PI3Ks for activation it needs a stimulus and leads to phosphorylation of several different substrates. On the other hand, the activity of ATM can be regulated via some of these substrates. Indeed, they provide a platform for ATM. In the area of damaged DNA, ATM takes part in the phosphorylation of the histone variant H2AX, resulting in production of γH2AX. ATM then phosphorylates the adapter protein MDC1. These phosphorylation events form a docking station for many elements involved in the DNA damage repair system, including the RING-finger ubiquitin ligase, RNF8 that binds to phosphorylated MDC1. RNF8 then leads to ubiquitation of γH2AX, resulting in its stabilization. Stabilized γH2AX is the required platform for recruitment of p53 binding protein 1 (53 BP1) and BRCA1. Following their recruitment, 53BP1 and BRCA1 get phosphorylated by ATM, activating DNA repair processes. ATM also interacts with the MRN complex elements, such as MRE11, NBS1 and Rad50, which bind to double strand DNA and act together as a sensor of DNA damage. This interaction leads to an effective response to DNA damage. In the next levels of ATM dependent mechanisms, p53 transactivates its target genes including CDK inhibitor p21, resulting in the inhibition of the Cyclin-CDK complex formation and hindering G1 to S phase transition. mdm2 which negatively regulates p53, is also phosphorylated by ATM, resulting in abrogation of its interacting potential and stabilization of p53. If occurred in S-phase, DNA DSBs triggers CHK2 activation (phosphorylation on threonine 68) by ATM, leading to the phosphorylation of CDC25A, causing its degradation. Genomic stability is also regulated by ATM where it activates Akt, triggering active Skp that in turn regulates the critical replication licensing factor, Cdt. This process is vital for the maintenance of genome by licensing only one replication event in any given region.

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ATM gene variants in brain tumors.

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Three hit hypothesis. Two novel heterozygously intronic alteration, i.e., IVS 38- 63 T>A and IVS 38-30 A> was found in proband located within 3 regions of splicing site. Two non-inherited events including IVS38-63T>A and IVS38-30A>G, resulting from two separate courses of evolution in proband occurred on the same chromosome which was different from the inherited D1853N polymorphism (data is adopted from Mehdipour, et al. 2008).