Positive feedback of G1 cyclins ensures coherent cell cycle entry

In budding yeast, Saccharomyces cerevisiae, the Start checkpoint integrates multiple internal and external signals into an all- or- none decision to enter the cell cycle. Here we show that Start behaves like a switch due to systems- level feedback in the regulatory network. In contrast to current models proposing a linear cascade of Start activation, transcriptional positive feedback of the G1 cyclins Cln1 and Cln2 induces the near- simultaneous expression of the similar to 200- gene G1/ S regulon. Nuclear Cln2 drives coherent regulon expression, whereas cytoplasmic Cln2 drives efficient budding. Cells with the CLN1 and CLN2 genes deleted frequently arrest as unbudded cells, incurring a large fluctuation- induced fitness penalty due to both the lack of cytoplasmic Cln2 and insufficient G1/ S regulon expression. Thus, positive- feedback- amplified expression of Cln1 and Cln2 simultaneously drives robust budding and rapid, coherent regulon expression. A similar G1/ S regulatory network in mammalian cells, comprised of non- orthologous genes, suggests either conservation of regulatory architecture or convergent evolution.