Dataset Information

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.

SUBMITTER: de Gooijer MC

PROVIDER: S-EPMC5377395 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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The G2 checkpoint-a node-based molecular switch.

de Gooijer Mark C MC van den Top Arnout A Bockaj Irena I Beijnen Jos H JH Würdinger Thomas T van Tellingen Olaf O

FEBS open bio 20170304 4

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 ...[more]

PMID: 28396830

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Project description:Comparative phosphoproteomic analysis of checkpoint recovery identifies new regulators of the DNA damage response. How cells recover from a DNA damage-induced arrest is currently poorly understood. We have performed large-scale quantitative phosphoproteomics to identify changes in protein phosphorylation that occur during recovery from a G2 arrest. We identified 154 proteins that were differentially phosphorylated in multiple experiments. Systematic depletion of each of these differentially phosphorylated proteins by siRNA identified at least 10 potential regulators of recovery. Data processing and bioinformatics: Raw data were converted to single DTA files using DTA SuperCharge and merged into Mascot Generic Format (MGF) files, which were searched using an in-house licensed Mascot v2.2 search engine against Human Swissprot 56.2 database concatenated with reversed sequences as decoy (containing 40656 sequences, 20328 forward sequences). Carbamidomethyl cysteine and oxidized methionines were set as fixed modifications; serine, threonine, and tyrosine phosphorylations were set as variable modifications; quantification was set with dimethyl double mode. The mass tolerance of the precursor ion was 10 ppm and 0.9 Da for fragment ions. The false discovery rate (FDR) was determined as < 1% (Mascot score threshold of 31) using the decoy database approach and the MGF files were trimmed at Mascot score threshold of 31 (1% FDR) by RockerBox. MSQuant v1.5 was used to quantitate the amounts of the identified phosphopeptides and determine the exact phosphorylation site within the peptide. Every phosphopeptide quantitation was manually validated; peptides with low signal:noise ratios, low number of MS scans, or overlapping peaks were not included for quantitative purposes. Histogram plots of the ratio of whole quantified peptides in each experiment were used to normalize the ratios. A program to extract information from MSQuant output was developed in-house to identify the position of each phosphorylation site and its status in current available databases (Phospho ELM and SwissProt). Panther Classification System was used to classify proteins with regulated phosphopeptides. NetworKIN was used to predict in vivo kinases for the phosphosites.

Dataset Information

The G2 checkpoint-a node-based molecular switch.

Publications

The G2 checkpoint-a node-based molecular switch.

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