DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation

Area of Science:

• Cellular biology
• Molecular biology
• Biochemistry

Background:

• ATM protein kinase is essential for mammalian cell response to ionizing radiation.
• Mutations in ATM are linked to the human genetic disorder ataxia-telangiectasia.

Purpose of the Study:

• To elucidate the mechanism of ATM protein kinase activation following ionizing radiation exposure.
• To investigate the role of ATM autophosphorylation and multimerization in DNA damage response.

Main Methods:

• Studied ATM protein kinase activity in mammalian cells after irradiation.
• Utilized autophosphorylation assays and antibody binding to detect ATM activation.
• Investigated the relationship between DNA double-strand breaks and ATM activation.

Main Results:

• ATM exists as an inactive dimer or multimer in unirradiated cells, with its kinase domain bound to the FAT domain.
• Ionizing radiation triggers rapid intermolecular autophosphorylation of serine 1981, causing dimer dissociation and activating ATM kinase.
• ATM activation occurs at low radiation doses and is detectable with few DNA double-strand breaks, suggesting chromatin structural changes rather than direct DNA binding initiate activation.

Conclusions:

• ATM kinase activation is an early event in cellular response to irradiation.
• ATM activation is mediated by autophosphorylation-induced dimer dissociation, not direct binding to DNA breaks.
• Chromatin structural changes likely play a role in initiating ATM activation.