A Mitotic Phosphorylation Feedback Network Connects Cdk1, Plk1, 53BP1, and Chk2 to Inactivate the G2/M DNA Damage Checkpoint
van Vugt, Marcel A. T. M.
Gardino, Alexandra K.
Reinhardt, H. Christian
Tan, Chris S.
Keezer, Susan M.
Carr, Steven A.
Smerdon, Stephen J.
Brummelkamp, Thijn R.
Lewis, Timothy A.
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Citationvan Vugt, Marcel A. T. M., Alexandra K. Gardino, Rune Linding, Gerard J. Ostheimer, H. Christian Reinhardt, Shao-En Ong, Chris S. Tan, et al. 2010. A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G2/M DNA damage checkpoint. PLoS Biology 8(1): e1000287.
AbstractDNA damage checkpoints arrest cell cycle progression to facilitate DNA repair. The ability to survive genotoxic insults
depends not only on the initiation of cell cycle checkpoints but also on checkpoint maintenance. While activation of DNA
damage checkpoints has been studied extensively, molecular mechanisms involved in sustaining and ultimately inactivating
cell cycle checkpoints are largely unknown. Here, we explored feedback mechanisms that control the maintenance and
termination of checkpoint function by computationally identifying an evolutionary conserved mitotic phosphorylation
network within the DNA damage response. We demonstrate that the non-enzymatic checkpoint adaptor protein 53BP1 is
an in vivo target of the cell cycle kinases Cyclin-dependent kinase-1 and Polo-like kinase-1 (Plk1). We show that Plk1 binds
53BP1 during mitosis and that this interaction is required for proper inactivation of the DNA damage checkpoint. 53BP1
mutants that are unable to bind Plk1 fail to restart the cell cycle after ionizing radiation-mediated cell cycle arrest.
Importantly, we show that Plk1 also phosphorylates the 53BP1-binding checkpoint kinase Chk2 to inactivate its FHA domain
and inhibit its kinase activity in mammalian cells. Thus, a mitotic kinase-mediated negative feedback loop regulates the
ATM-Chk2 branch of the DNA damage signaling network by phosphorylating conserved sites in 53BP1 and Chk2 to
inactivate checkpoint signaling and control checkpoint duration.
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