Polo-like Kinase-1 Controls Recovery from a G2 DNA Damage-Induced Arrest in Mammalian Cells

Abstract

DNA damage triggers multiple checkpoint pathways to arrest cell cycle progression. Less is known about the mechanisms that allow resumption of the cell cycle once checkpoint signaling is silenced. Here we show that while in undamaged cells several redundant pathways can promote the onset of mitosis, this redundancy is lost in cells recovering from a DNA damage-induced arrest. We demonstrate that Plk1 is crucial for mitotic entry following recovery from DNA damage. However, Plk1 is no longer required in cells depleted of Wee1, and we could show that Plk1 is involved in the degradation of Wee1 at the onset of mitosis. Thus, our data show that the cell cycle machinery is reset in response to DNA damage and that cells become critically dependent on Plk1-mediated degradation of Wee1 for their recovery.

Protein kinases controlling the onset of mitosis

“…On the other hand, the presence of potential phosphorylation sites for Chk1 or Chk2 suggests that Plk1 may be targeted by checkpoint kinases [100], an issue that has not been explored to date. In line with the evidence obtained in yeast, subsequent studies addressed the role of Plk1 during recovery from DNA damage [101]. Since the mechanism of recovery from DNA damage is still not fully understood in its molecular details, in the study conducted on human cells [101] recovery was mimicked by interrupting the flow of DNA damage signals with the ATM/ATR inhibitor caffeine.…”

“…In line with the evidence obtained in yeast, subsequent studies addressed the role of Plk1 during recovery from DNA damage [101]. Since the mechanism of recovery from DNA damage is still not fully understood in its molecular details, in the study conducted on human cells [101] recovery was mimicked by interrupting the flow of DNA damage signals with the ATM/ATR inhibitor caffeine. In this setting, Plk1 was shown to facilitate resumption of cell cycle progression and mitotic entry.…”

Centrosomes as signalling centres

“…Thus, entry into M phase requires both inhibition of Wee1-related kinases and activation of Cdc25 phosphatases (figure 2a). This is brought about by Polo-like kinase 1 (Plk1; Plo1 in fission yeast), which phosphorylates both Cdc25 and Wee1 [37][38][39][40], with the result that Cdc25 is activated whilst Wee1 is inhibited-in fact targeted for degradation [41] ( figure 2a,c). Importantly, the recruitment of Plk1 to both Wee1 and Cdc25 depends on prior phosphorylation of these enzymes by an initial pool of activated Cdk1.…”

Knockdown of Cdc25B in Renal Cell Carcinoma is Associated with Decreased Malignant Features

“…Cdc25B is activated in G2 phase and is responsible for the activation of cyclin A/Cdk2 in G2 phase (Goldstone et al, 2001) and initiation of cyclin B/Cdk1 activation and mitotic entry (Gabrielli et al, 1996;Karlsson et al, 1999;Loffler et al, 2006). It also has a unique function in recovery from a G2-phase checkpoint arrest (van Vugt et al, 2004). A number of mechanisms can regulate Cdc25B, including its…”