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Molecules involved in DNA replication
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Molecular Interaction Map of modulation of DNA replication by ATM pathway after radiation

Modulation of DNA replication by the ATM pathway after irradiation or induction of double strand breaks

Mirit Aladjem, Stephania Pasa, Yves Pommier and Kurt W. Kohn
Implemented by : Margot Sunshine, Hong Cao and David Kane
Irradiation or double strand breaks lead to the activation of the ATM pathway in cells in which this pathway is intact. ATM kinase phosphorylates CHK2. This phosphorylation inhibits CDC25, a phosphatase required to remove inhibitory phosphorylation of cyclin dependent kinases. Since CDKs cannot be activated, initiation of DNA replication and progression through the cell cycle cannot occur. In parallel, CHK2 also phosphorylates DDK (hsk1/dpf4) and this phosphorylation inhibits binding of the MCM complex to ORC-bound chromatin. Finally, there is some evidence suggesting a third pathway mediated by ATM that inhibits CDC45 binding to licensed chromatin. All three sets of molecular interactions result in the coherent inhibition of DNA replication from chromatin even if licensing (binding of the MCM complex) had already taken place. ATM kinase also activates the p53-mediated pathway that may lead to further kinase inhibition and apoptosis.
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