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Published on: January 20, 2015
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Christopher J Bakkenist1, Michael B Kastan
1Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105, USA.
Abstract:
The ATM protein kinase, mutations of which are associated with the human disease ataxia-telangiectasia, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described 'FAT' domain. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation, and our data indicate that ATM activation is not dependent on direct binding to DNA strand breaks, but may result from changes in the structure of chromatin.
Insights
The ATM protein kinase, crucial for DNA damage response, is activated by ionizing radiation. Irradiation causes ATM to autophosphorylate, leading to dimer dissociation and initiating kinase activity for cellular repair.
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.
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