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 approximately 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.
Skotheim
Jan M
JM
Center for Studies in Physics and Biology, The Rockefeller University, New York 10065, USA. skotheim@stanford.edu
Di Talia
Stefano
S
Siggia
Eric D
ED
Cross
Frederick R
FR
D002453:Cell Cycle / Q000502:physiology*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D016193:G1 Phase; D015966:Gene Expression Regulation, Fungal; D008938:Mitosis; D010766:Phosphorylation; D018085:Regulon / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C082719:CLN1 protein, S cerevisiae; C082721:CLN2 protein, S cerevisiae; D016213:Cyclins; C083209:MBP1 protein, S cerevisiae; D012097:Repressor Proteins; C081540:SBF protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C508130:Whi5 protein, S cerevisiae