Ataxia-telangiectasia mutated (ATM) (ATM)

Ataxia-telangiectasia mutated (ATM) is a high-molecular-weight serine/threonine protein kinase that belongs to the phosphatidylinositol 3-kinase-related kinase (PIKK) family. It functions as a master regulator of the DNA damage response (DDR), specifically responding to DNA double-strand breaks (DSBs) caused by ionizing radiation or genotoxic agents. Upon recruitment to damage sites by the MRN complex, ATM undergoes autophosphorylation and monomerization, subsequently phosphorylating a vast network of downstream substrates including p53, Chk2, and H2AX. These phosphorylation events trigger cell cycle arrest, facilitate DNA repair through homologous recombination, or induce apoptosis if the damage is irreparable. Mutations in the ATM gene are the underlying cause of Ataxia-telangiectasia, a multisystem disorder characterized by neurodegeneration, immunodeficiency, and a high predisposition to cancer. In the context of oncology, ATM is a prominent therapeutic target; pharmacological inhibition of its kinase activity is used to sensitize tumor cells to radiotherapy and chemotherapy by blocking their primary DNA repair mechanism. Current drug development focuses on highly selective small-molecule inhibitors, such as AZD1390 and M4076, which are being evaluated in clinical trials for various solid tumors and hematological malignancies.

Other names

ATM serine/threonine kinaseSerine-protein kinase ATMA-T mutatedTEL1TELO1AT1ATAATCATDATDCATE

ATM kinase inhibition, which prevents the phosphorylation of downstream effectors in the DNA damage response pathway, thereby impairing double-strand break repair and sensitizing cells to DNA-damaging agents.