Positive feedback of G1 cyclins ensures coherent cell cycle entry

Jan M. Skotheim (), Stefano Di Talia, Eric D. Siggia and Frederick R. Cross
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Jan M. Skotheim: Center for Studies in Physics and Biology, The Rockefeller University,
Stefano Di Talia: Center for Studies in Physics and Biology, The Rockefeller University,
Eric D. Siggia: Center for Studies in Physics and Biology, The Rockefeller University,
Frederick R. Cross: The Rockefeller University, 1230 York Avenue, New York 10065, USA

Nature, 2008, vol. 454, issue 7202, 291-296

Abstract: Abstract 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 ∼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.

Date: 2008
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DOI: 10.1038/nature07118

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