Cyclin-Dependent Kinases Are Regulators and Effectors of Oscillations Driven by a Transcription Factor Network

Abstract

In our mathematical model of a transcription factor network, we inadvertently reported the wrong logic rules for the TF, YHP1 in Figure 3A. In each column (A-D), the logic should read, ''MCM1 n SBF n HCM1 ^: ASH1'' (instead of ''n : ASH1''). Note also that activation edges from MCM and HCM1 to YHP1 were unintentionally omitted from the network graphs depicted in Figures 2J and S2A. Finally, in Figure 3C, the distributions for the attractors using activation logic ''D'' should be 35.94%, 64.06%, and 0.00%, respectively, for the attractors 1, 2, and 3.The updated versions of the figures are provided below. We apologize for any confusion these errors may have caused.

Topology and Control of the Cell-Cycle-Regulated Transcriptional Circuitry

“…In addition, the program of transcription repeated in a second cycle, despite the fact that the cells were arrested at the G1/S border by all conventional cell cycle measures. In a later study, similar results were observed in cdc28-4 cells at restrictive temperature, although the number and amplitude of the periodic genes was substantially reduced (Simmons Kovacs et al 2012).…”

“…Although these factors do not play a direct role in limiting G1/S transcription via feedback, Hcm1 indirectly activates Clb2, the feedback repressor of SBF genes, via its role in the expression of Fkh2 and Ndd1 activators of the G2/M gene cluster (Figure 1). Despite the central role of Hcm1 in the regulation of genes involved in cell-cycleregulated transcription, hcm1 mutants are viable and retain detectable periodicity of S phase gene expression (Pramila et al 2006;Simmons Kovacs et al 2012). This suggests the involvement of additional, as yet unknown, transcription factors in the regulation of this gene family.…”

“…Thus, post-transcriptional regulation by CDKs may act more like a rheostat in the control of periodic transcription rather than simply functioning as an "on-off" switch. In general, as CDK activities decreased, the number of identifiable periodic genes also decreased (Simmons Kovacs et al 2012). Furthermore, decreasing CDK activity was associated with diminished transcript amplitudes as well as increasing oscillatory periods.…”

“…Furthermore, decreasing CDK activity was associated with diminished transcript amplitudes as well as increasing oscillatory periods. The regulatory mechanisms responsible for the loss of amplitude and increased period may be positive feedback loops in which cyclin expression is promoted by a transcription factor that is then phosphorylated by the cyclin/CDK complex, which increases the transcription factor's activity (Simmons Kovacs et al 2012). This regulatory network motif affects both G1 (SBF and Cln2; see section titled "Activation of G1/S transcription factors") (Cross and Tinkelenberg 1991;Dirick and Nasmyth 1991;Skotheim et al 2008) and G2/M gene clusters (Pic-Taylor et al 2004).…”

“…Furthermore, the inhibition of Swi5/Ace2-regulated genes by mitotic cyclin/CDK ensures that the initiation of a new program of G1 transcription is dependent on exit from mitosis and the subsequent loss of Clb2/CDK activity. Thus, transcription factor networks and CDKs collaborate to coordinate the execution of the transcriptional program with the cell cycle (Simmons Kovacs et al 2012).…”