The G2 checkpoint—a node‐based molecular switch

Abstract

Tight regulation of the eukaryotic cell cycle is paramount to ensure genomic integrity throughout life. Cell cycle checkpoints are present in each phase of the cell cycle and prevent cell cycle progression when genomic integrity is compromised. The G2 checkpoint is an intricate signaling network that regulates the progression of G2 to mitosis (M). We propose here a node‐based model of G2 checkpoint regulation, in which the action of the central CDK1–cyclin B1 node is determined by the concerted but opposing activities of the Wee1 and cell division control protein 25C (CDC25C) nodes. Phosphorylation of both Wee1 and CDC25C at specific sites determines their subcellular localization, driving them either toward activity within the nucleus or to the cytoplasm and subsequent ubiquitin‐mediated proteasomal degradation. In turn, this subcellular balance of the Wee1 and CDC25C nodes is directed by the action of the PLK1 and CHK1 nodes via what we have termed the ‘nuclear and cytoplasmic decision states’ of Wee1 and CDC25C. The proposed node‐based model provides an intelligible structure of the complex interactions that govern the decision to delay or continue G2/M progression. The model may also aid in predicting the effects of agents that target these G2 checkpoint nodes.

The new 6q27 tumor suppressor DACT2, frequently silenced by CpG methylation, sensitizes nasopharyngeal cancer cells to paclitaxel and 5-FU toxicity via β-catenin/Cdc25c signaling and G2/M arrest

“…In addition, the gene coding for cell division control protein 25C (Cdc25c), a regulator of G2/M cell cycle progression, has a LEF1 binding site on its promoter region. The function of that protein may thus be responsive to Wnt/β-catenin signaling activity [ 14 , 15 ]. It is thus reasonable that DACT2 inhibits the activity of β-catenin/LEF1 complex by competitively binding with β-catenin followed by downregulation of Cdc25c, which ultimately blocks cell division in the G2/M phase.…”

Triggering mitosis

“…The ultimate on and off switch of Cdk1 in interphase is mediated by inhibitory phosphorylations at Thr14 and Tyr15 that are maintained by the Wee1/Myt1 kinases . Removal of these inhibitory phosphate groups by the dual‐specific Cdc25 phosphatases triggers mitotic entry . This regulatory mechanism ensures that the steady rise of mitotic cyclins in interphase is translated into a sharp ultrasensitive signal response of Cdk1 activity at the onset of mitosis .…”

“…In fact, these enzymes are regulated in multiple ways. The major control elements for both Wee1 and Cdc25 regulation include activation and inhibition of phosphorylation by various kinases (Chk1, CK1, Cdk1, Cdk2 and Plk1); dephosphorylations by PP1, PP2A:B55, PP2A:B56 and Cdc14; binding to 14‐3‐3 proteins; proteolysis; and proline isomerisation . For more details on the regulatory mechanisms involving Wee1 and Cdc25s, see Figs and .…”

Caffeine stabilises fission yeast Wee1 in a Rad24-dependent manner but attenuates its expression in response to DNA damage identifying a putative role for TORC1 in mediating its effects on cell cycle progression

“…In contrast, Wee1 phosphorylates Cdc2 on tyrosine residue 15 to inhibit its activity. Cdc2 in turn negatively regulates Wee1 by phosphorylation leading to its nuclear exclusion or degradation (Caspari & Hilditch, 2015, Moseley, 2017, de Gooijer et al, 2017. Cells must delay progress through Sphase and mitosis in response to stalled replication, DNA double strand breaks and other forms of damage, in order to effect DNA repair and maintain viability (Karlsson-Rosenthal & Millar, 2006, Alao & Sunnerhagen, 2008.…”

“…The integration of Cdc25 and Wee1 phosphorylation, localisation, stability and activity thus play a key role in modulating the timing of mitosis. TORC1, Rad3 and Sty1 regulate the major signalling pathways that converge on the Cdc25 and Wee1 axis (Alao & Sunnerhagen, 2008, Petersen, 2009, de Gooijer et al, 2017. Herein we further explored the mechanism(s) by which caffeine stabilises Cdc25 and overrides checkpoint signalling, and have investigated the impact of subcellular localisation under these conditions.…”