The Start checkpoint is a major cell cycle

Cell cycle

The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...

 checkpoint in yeast. The Start checkpoint ensures irreversible cell-cycle entry even if conditions later become unfavorable. The physiological factors that control passage through the Start checkpoint include external nutrient concentrations, presence of mating factor/ pheromone, forms of stress, and size control.

Cell Nutrient Growth and Size Control

The external nutrient concentrations are extremely important to proceeding through the Start checkpoint. The availability of nutrients is strongly correlated to cell growth size. Cells will not proceed if they do not reach a certain size due to nutrient deprivation, usually nitrogen. Thus, larger cells spend less time in the Start checkpoint compared to smaller cells.

Transcription of G1/S Genes

The transcription of several G1/S genes is essential for cells to proceed through the cell cycle. In budding yeast, the transcription of over 200 genes is activated at the G1/S transition.
The transcription of these G1/S genes is primarily regulated by two gene regulatory proteins, SBF and MBF. These regulatory proteins form complexes with SCB and MCB, respectively, which are located on the promoters of G1/S genes.

SBF and MBF Regulatory Proteins

The SBF and MBF complexes are able to activate G1/S transcription only if an inhibitor protein known as Whi5 is dissociated. The dissociation of Whi5 requires phosphorylation by a Cln3-Cdk1

Cdk1

Cyclin dependent kinase 1 also known as Cdk1 or cell division control protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S....

 complex. This indicates that the activity of Cln3-Cdk1 plays an important role in the Start checkpoint because of its necessity to simultaneously activate both SBF and MBF proteins. The activity of Cln3

CLN3

Battenin is a protein that in humans is encoded by the CLN3 gene located on chromosome 16.- Function :Battenin is involved in lysosomal function. Many alternatively spliced transcript variants have been found for this gene.-Clinical significance:...

 correlates with cell growth rate.

Activation of S-Cdks by G1/S-Cdks

G1/S genes include the cyclins Cln1 and Cln2, which can form active complexes with Cdk1. These activated Cln-Cdk complexes help activate S-Cdk complexes, which are normally inhibited by Sic1. Sic1 has no effect on the Cln-Cdk complexes. The Cln-Cdk complexes activate the S-Cdk complexes through the destruction of Sic1

Sic1

Sic1, a protein, is a stoichiometric inhibitor of Cdk1-Clb complexes in the budding yeast Saccharomyces cerevisiae. Because B-type cyclin-Cdk1 complexes are the drivers of S-phase initiation, Sic1 prevents premature S-phase entry...

 by phosphorylation

Phosphorylation

Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

 and subsequent SCF ubiquitination.

Mating Factor/ Pheromone

The presence of mating pheromone leads to cell cycle arrest by activating Far1, a protein that inhibits G1/S-Cdks. The Far1 proteins act in inhibiting Cln-Cdks (Cln-Cdc28) when an mating factor is present. This can be contrasted to Sic1, which inhibits Clb-Cdks.Because the Cln-Cdks are inhibited, the S-Cdks remain inactive and the cell cycle is arrested at the Start checkpoint.

Further Research

Further research by the Skotheim Lab at Stanford University provides that the Start checkpoint acts like a switch due to feedback regulatory mechanisms. They propose that a positive feedback mechanism is responsible for the coherent expression of the 200 G1/S genes in yeast. In fact, they show that Cln1,2-dependent positive feedback and Whi5 dissociation is crucial to progression through the Start checkpoint and subsequent cell cycle commitment.