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Molecules involved in DNA replication
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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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