Phosphorylation of mini-chromosome maintenance 3 (MCM3) by Chk1 negatively regulates DNA replication and checkpoint activation [Cell Biology]

March 25th, 2015 by Han, X., Pozo, F. M., Wisotsky, J. N., Wang, B., Jacobberger, J. W., Zhang, Y.

Mechanisms controlling DNA replication and replication checkpoint are critical for the maintenance of genome stability and the prevention or treatment of human cancers. Chk1 is a key effector protein kinase that regulates DNA damage response and replication checkpoint. The heterohexamic mini-chromosome maintenance (MCM) complex is the core component of mammalian DNA helicase and has been implicated in replication checkpoint activation. Here we report that Chk1 phosphorylates the MCM3 subunit of the MCM complex at Ser-205 under normal growth conditions. Mutating the Ser-205 of MCM3 to Ala increased the length of DNA replication track and shortened the S phase duration, indicating that Ser-205 phosphorylation negatively controls normal DNA replication. Upon replicative stress treatment, the inhibitory phosphorylation of MCM3 at Ser-205 is reduced and this reduction is accompanied with the generation of single strand DNA (ssDNA), the key platform for ATR activation. As a result, the replication checkpoint is activated. Together, these data provide significant insights into the regulation of both normal DNA replication and replication checkpoint activation through the novel phosphorylation of MCM3 by Chk1.
  • Posted in Journal of Biological Chemistry, Publications
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