Sic1 as a timer of Clb cyclin waves in the yeast cell cycle – design principle of not just an inhibitor

Abstract

Cellular systems biology aims to uncover design principles that describe the properties of biological networks through interaction of their components in space and time. The cell cycle is a complex system regulated by molecules that are integrated into functional modules to ensure genome integrity and faithful cell division. In budding yeast, cyclin-dependent kinases (Cdk1/Clb) drive cell cycle progression, being activated and inactivated in a precise temporal sequence. In this module, which we refer to as the 'Clb module', different Cdk1/Clb complexes are regulated to generate waves of Clb activity, a functional property of cell cycle control. The inhibitor Sic1 plays a critical role in the Clb module by binding to and blocking Cdk1/Clb activity, ultimately setting the timing of DNA replication and mitosis. Fifteen years of research subsequent to the identification of Sic1 have lead to the development of an integrative approach that addresses its role in regulating the Clb module. Sic1 is an intrinsically disordered protein and achieves its inhibitory function by cooperative binding, where different structural regions stretch on the Cdk1/Clb surface. Moreover, Sic1 promotes S phase entry, facilitating Cdk1/Clb5 nuclear transport, and therefore revealing a double function of inhibitor/activator that rationalizes a mechanism to prevent precocious DNA replication. Interestingly, the investigation of Clb temporal dynamics by mathematical modelling and experimental validation provides evidence that Sic1 acts as a timer to coordinate oscillations of Clb cyclin waves. Here we review these findings, focusing on the design principle underlying the Clb module, which highlights the role of Sic1 in regulating phase-specific Cdk1/Clb activities.

Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae

“…6c). Consistently, mRNA levels for the corresponding genes were downregulated upon VPA exposure (Supplementary Table S1), and expression of the Clb5/Clb6-CDK inhibitor Sic1, whose stability is downregulated in a Cln1/2-CDK manner46, was maintained in cells released from G1 in VPA-containing SC (Fig. 6c).…”

A Clb/Cdk1-mediated regulation of Fkh2 synchronizes CLB expression in the budding yeast cell cycle

“…1a) 12 as well as of the newly unraveled transcriptional cascade activating CLB genes to the waves of Clb activation, we employed an independent, qualitative modeling approach, the Boolean modeling, to identify the possible network structure(s) able to reproduce this oscillatory behavior. A prior knowledge network (PKN) of the interactions among four nodes encompassing the mitotic cyclins Clb5, Clb3 and Clb2, and the cyclin-dependent inhibitor Sic1 24 was modeled (Fig. 5a) following the strategy shown in Fig.…”

Cancer/Testis Antigens: “Smart” Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers

“…The structural plasticity and conformational adaptability of IDPs/IDPRs, their ability to react and change easily and quickly in response to the changes in their environment, their capability to fold under the variety of conditions [53,54,55,60,61,62,63,64,65,66,67,68,69] combined with their binding promiscuity and unique capability to fold differently while interacting with different binding partners [66,70] define a wide set of functions exerted by IDPs/IDPRs in different biological systems. These same features determine the broad participation of IDPs/IDPRs in various biological processes [59,71,72] where they are involved in numerous signaling processes [73,74], regulation of different cellular pathways [75,76,77,78,79,80], cell protection [81], protein protection [82,83], cellular homeostasis [84,85] and cell cycle regulation [86,87,88,89,90]. Thus, biological activities of many IDPs/IDPRs are known to be precisely and tightly controlled and regulated by extensive posttranslational modifications (PTMs), such as phosphorylation, acetylation, glycosylation, etc.…”