Dynamics of SIN Asymmetry Establishment

Abstract

Timing of cell division is coordinated by the Septation Initiation Network (SIN) in fission yeast. SIN activation is initiated at the two spindle pole bodies (SPB) of the cell in metaphase, but only one of these SPBs contains an active SIN in anaphase, while SIN is inactivated in the other by the Cdc16-Byr4 GAP complex. Most of the factors that are needed for such asymmetry establishment have been already characterized, but we lack the molecular details that drive such quick asymmetric distribution of molecules at the two SPBs. Here we investigate the problem by computational modeling and, after establishing a minimal system with two antagonists that can drive reliable asymmetry establishment, we incorporate the current knowledge on the basic SIN regulators into an extended model with molecular details of the key regulators. The model can capture several peculiar earlier experimental findings and also predicts the behavior of double and triple SIN mutants. We experimentally tested one prediction, that phosphorylation of the scaffold protein Cdc11 by a SIN kinase and the core cell cycle regulatory Cyclin dependent kinase (Cdk) can compensate for mutations in the SIN inhibitor Cdc16 with different efficiencies. One aspect of the prediction failed, highlighting a potential hole in our current knowledge. Further experimental tests revealed that SIN induced Cdc11 phosphorylation might have two separate effects. We conclude that SIN asymmetry is established by the antagonistic interactions between SIN and its inhibitor Cdc16-Byr4, partially through the regulation of Cdc11 phosphorylation states.

Pombe's thirteen – control of fission yeast cell division by the septation initiation network

“…Consistent with this view, laser ablation of the new SPB (nSPB) in anaphase results in association of Cdc7p with the old SPB (oSPB) (Magidson et al, 2006), suggesting that the SPBs communicate during mitosis. Computational modelling (Bajpai et al, 2013) produced results consistent with the notion that asymmetric protein segregation is established by antagonistic interactions between the SIN kinases and Byr4p-Cdc16p, which act in part by regulating Cdc11p phosphorylation.…”

“…Once the phosphorylation sites on SIN proteins and their substrates have been determined, mutants will help us to understand their regulatory significance. Now that many of the regulatory relationships between the SIN proteins have been established, further mathematical modelling of the SIN will be useful as an aid to better describe our observations (Csikász-Nagy et al, 2007) and to make predictions that can be tested at the bench (Bajpai et al, 2013). Studies on the counterparts of the SIN in other organisms will also provide new hypotheses to test in S. pombe; for example, is the assembly of SIN proteins at the SPB also a phosphorylation-dependent event, as in the mitotic exit network of the budding yeast (Rock et al, 2013)?…”

Analysis ofS. pombeSIN protein SPB-association reveals two genetically separable states of the SIN

“…If the SIN fails to signal, then SIN protein asymmetry in anaphase is not established. Therefore, it has been proposed that there is a feedback loop within the SIN, mediated by Sid2p and that phosphorylation of the scaffold protein Cdc11p by Sid2p contributes to this regulation (Bajpai et al, 2013;Feoktistova et al, 2012;Johnson et al, 2012).…”

Efficient Switches in Biology and Computer Science

“…A whole population of histones thus switches between methylation/acetylation states, generating a switch-like behaviour exactly matching that of the AM network (Fig 5A). Other highly investigated biological switches with two positive feedback loops include the lambda phage lytic-lysogenic switch [62], polarity establishment [63], and symmetry breaking [64]. Among these, the asymmetric activation of the septation initiation network in fission yeast shows a network structure (SI) that contains a double positive and a double negative feedback loop, leading to the exact same dynamics as AM (Fig 5C).…”

“…(B) The polarity regulatory model of Motegi et al (2013) [63]. (C) The septation initiation network asymmetry establishment model of Bajpai et al (2013) [64]. The middle panels show the respective models with the condensed network notation, in which each node (molecule) represents three forms: inactive, non-decided, and active (Fig 2); the right panels show the behaviour of the models when initiated from equal initial conditions and simulated with equal parameter values (all rates = 1).…”