Recovery from a DNA-damage-induced G2 arrest requires Cdk-dependent activation of FoxM1.
Activation of the DNA-damage checkpoint culminates in the inhibition of cyclin-dependent kinase (Cdk) complexes to prevent cell-cycle progression. We have shown recently that Cdk activity is required for activation of the Forkhead transcription factor FoxM1, an important regulator of gene expression in the G2 phase of the cell cycle. Here, we show that FoxM1 is transcriptionally active during a DNA-damage-induced G2 arrest and is essential for checkpoint recovery. Paradoxically, Cdk activity, although reduced after checkpoint activation, is required to maintain FoxM1-dependent transcription during the arrest and for expression of pro-mitotic targets such as cyclin A, cyclin B and Plk1. Indeed, we find that cells need to retain sufficient levels of Cdk activity during the DNA-damage response to maintain cellular competence to recover from a DNA-damaging insult.
Alvarez-Fernández
Mónica
M
Department of Medical Oncology, UMC Utrecht, Universiteitsweg 100, Stratenum 2.118, Utrecht 3584 CG, The Netherlands.
Halim
Vincentius A
VA
Krenning
Lenno
L
Aprelia
Melinda
M
Mohammed
Shabaz
S
Heck
Albert J
AJ
Medema
René H
RH
D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004249:DNA Damage; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016195:G2 Phase; D006801:Humans; D014158:Transcription, Genetic
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D018844:Cyclin-Dependent Kinases