ATM serine/threonine kinase

47211920ENSG00000149311ENSMUSG00000034218Q13315Q62388NM_001351836NM_007499NP_000042NP_001338763NP_001338764NP_001338765NP_000042.3NP_031525ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks (canonical pathway), oxidative stress, topoisomerase cleavage complexes, splicing intermediates, R-loops and in some cases by single-strand DNA breaks.

In 1995, the gene was discovered by Yosef Shiloh[6] who named its product ATM since he found that its mutations are responsible for the disorder ataxia–telangiectasia.

[7] In 1998, the Shiloh and Kastan laboratories independently showed that ATM is a protein kinase whose activity is enhanced by DNA damage.

Damages result from errors during replication, by-products of metabolism, general toxic drugs or ionizing radiation.

ATM plays a role in cell cycle delay after DNA damage, especially after double-strand breaks (DSBs).

[10] ATM is recruited to sites of double strand breaks by DSB sensor proteins, such as the MRN complex.

In the non-canonical pathway, e.g. through simulation by oxidative stress, the dimer can be activated by the formation of disulfide bonds.

Activated CHK2 phosphorylates phosphatase CDC25A, which is degraded thereupon and can no longer dephosphorylate CDK1-cyclin B, resulting in cell-cycle arrest.

Activation of ATM by the MRN complex is preceded by at least two steps, i.e. recruitment of ATM to DSB ends by the mediator of DNA damage checkpoint protein 1 (MDC1) which binds to MRE11, and the subsequent stimulation of kinase activity with the NBS1 C-terminus.

The acetylation occurs in the C-terminal half of the PRD domain and is required for ATM kinase activation and for its conversion into monomers.

One feature of the ATM protein is its rapid increase in kinase activity immediately following double-strand break formation.

AT patients have an increased risk for breast cancer that has been ascribed to ATM's interaction and phosphorylation of BRCA1 and its associated proteins following DNA damage.

[22] Mutations in the ATM gene are found at relatively low frequencies in sporadic cancers.

In squamous cell carcinoma of the head and neck, 42% of tumors displayed ATM promoter methylation.

[39] The wild-type ATM gene is expressed at a four-fold increased level in human testes compared to somatic cells (such as skin fibroblasts).

[41] In addition, impaired ATM-mediated DNA DSB repair has been identified as a likely cause of aging of mouse and human oocytes.

[43][44][45] One of the first discovered ATM inhibitors is caffeine with an IC50 of 0.2 mM and only a low selectivity within the PIKK family.

[50] Various optimisation efforts by AstraZeneca (AZD0156, AZD1390), Merck (M4076) and Dimitrov et al. have led to highly active ATM inhibitors with greater potency.

[78] Tefu, like ATM, is required for DNA repair and normal levels of meiotic recombination in oocytes.

Schematic illustration of the four known conserved domains in four members of the PIKKs family [ 13 ]
ATM-mediated two-step response to DNA double strand breaks. In the rapid response activated ATM phosphorylates effector kinase CHK2 which phosphorylates CDC25A, targeting it for ubiquitination and degradation. Therefore, phosphorylated CDK2-Cyclin accumulates and progression through the cell cycle is blocked. In the delayed response ATM phosphorylates the inhibitor of p53, MDM2, and p53, which is also phosphorylated by Chk2. The resulting activation and stabilization of p53 leads to an increased expression of Cdk inhibitor p21, which further helps to keep Cdk activity low and to maintain long-term cell cycle arrest. [ 15 ]
Caffeine is an ATM inhibitor with low activity
AZD0156 is a highly active ATM inhibitor from AstraZeneca