A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G(2)/M DNA damage checkpoint
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A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G(2)/M DNA damage checkpoint. / van Vugt, Marcel A T M; Gardino, Alexandra K; Linding, Rune; Ostheimer, Gerard J; Reinhardt, H Christian; Ong, Shao-En; Tan, Chris S; Miao, Hua; Keezer, Susan M; Li, Jeijin; Pawson, Tony; Lewis, Timothy A; Carr, Steven A; Smerdon, Stephen J; Brummelkamp, Thijn R; Yaffe, Michael B.
I: P L o S Biology (Online), Bind 8, Nr. 1, 01.2010, s. e1000287.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G(2)/M DNA damage checkpoint
AU - van Vugt, Marcel A T M
AU - Gardino, Alexandra K
AU - Linding, Rune
AU - Ostheimer, Gerard J
AU - Reinhardt, H Christian
AU - Ong, Shao-En
AU - Tan, Chris S
AU - Miao, Hua
AU - Keezer, Susan M
AU - Li, Jeijin
AU - Pawson, Tony
AU - Lewis, Timothy A
AU - Carr, Steven A
AU - Smerdon, Stephen J
AU - Brummelkamp, Thijn R
AU - Yaffe, Michael B
PY - 2010/1
Y1 - 2010/1
N2 - DNA 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.
AB - DNA 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.
KW - CDC2 Protein Kinase
KW - Cell Cycle Proteins
KW - Cell Division
KW - Cell Line
KW - Checkpoint Kinase 2
KW - DNA Damage
KW - Feedback, Physiological
KW - G2 Phase
KW - Humans
KW - Intracellular Signaling Peptides and Proteins
KW - Phosphorylation
KW - Protein-Serine-Threonine Kinases
KW - Proto-Oncogene Proteins
KW - Signal Transduction
U2 - 10.1371/journal.pbio.1000287
DO - 10.1371/journal.pbio.1000287
M3 - Journal article
C2 - 20126263
VL - 8
SP - e1000287
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 1
ER -
ID: 122677254