Cell cycle regulation by feed-forward loops coupling transcription and phosphorylation

Area of Science:

• Cell Biology
• Molecular Biology
• Systems Biology

Background:

• The eukaryotic cell cycle necessitates precise temporal control of hundreds of executor proteins (EPs) for cell growth and division.
• Cyclin-dependent protein kinases (Cdks) are critical regulators of EP production, activation, inactivation, and degradation.

Purpose of the Study:

• To identify and characterize feed-forward loops (FFLs) through which Cdk1 regulates EPs in budding yeast.
• To elucidate the role of FFLs in the temporal activation of EPs during the cell cycle.

Main Methods:

• Analysis of genome-scale data sets from budding yeast.
• Identification of 126 EPs regulated by Cdk1 via direct phosphorylation or transcription factor phosphorylation.
• Mathematical modeling to analyze FFL properties and predict EP activation timing.

Main Results:

• 126 EPs were identified as being regulated by Cdk1 through FFLs.
• Mathematical models demonstrated that FFLs can control EP activation timing based on regulatory signs (+/-).
• Case studies confirmed the predicted FFL-mediated regulation of specific EPs.

Conclusions:

• Feed-forward loops (FFLs) are a key mechanism by which Cdk1 orchestrates the temporal sequence of executor protein activities during the cell cycle.
• FFLs enable precise temporal control, allowing a few Cdk signals to drive complex cell cycle responses.
• This regulatory strategy ensures the correct temporal order of events essential for cell division.