The interplay between chromosome stability and cell cycle control explored through gene–gene interaction and computational simulation

Abstract

Chromosome stability models are usually qualitative models derived from molecular-genetic mechanisms for DNA repair, DNA synthesis, and cell division. While qualitative models are informative, they are also challenging to reformulate as precise quantitative models. In this report we explore how (A) laboratory experiments, (B) quantitative simulation, and (C) seriation algorithms can inform models of chromosome stability. Laboratory experiments were used to identify 19 genes that when over-expressed cause chromosome instability in the yeast Saccharomyces cerevisiae. To better understand the molecular mechanisms by which these genes act, we explored their genetic interactions with 18 deletion mutations known to cause chromosome instability. Quantitative simulations based on a mathematical model of the cell cycle were used to predict the consequences of several genetic interactions. These simulations lead us to suspect that the chromosome instability genes cause cell-cycle perturbations. Cell-cycle involvement was confirmed using a seriation algorithm, which was used to analyze the genetic interaction matrix to reveal an underlying cyclical pattern. The seriation algorithm searched over 1014 possible arrangements of rows and columns to find one optimal arrangement, which correctly reflects events during cell cycle phases. To conclude, we illustrate how the molecular mechanisms behind these cell cycle events are consistent with established molecular interaction maps.

A nitrogen source-regulated microprotein confers an alternative mechanism of G1/S transcriptional activation in budding yeast

“…In contrast, NSR1 deletion shows a positive genetic interaction with the RNA Pol II CTD-associated phosphatase, FCP1, which negatively regulates transcription (51). NSR1 overexpression also subtly increases chromosomal instability (52), which might result from premature Start activation (53). These interactions with transcriptional regulators are consistent with our proposed model for Nsr1 function in G1/S transcription activation.…”

The microprotein Nrs1 rewires the G1/S transcriptional machinery during nitrogen limitation in budding yeast

“…In contrast, NRS1 deletion shows a positive genetic interaction with the RNA Pol II CTD-associated phosphatase, FCP1, which negatively regulates transcription [ 63 ]. NRS1 overexpression also subtly increases chromosomal instability [ 64 ], which might result from premature Start activation [ 65 ]. These interactions with transcriptional regulators are consistent with our proposed model for Nrs1 function in G1/S transcription activation.…”

Cross-Species Complementation of Nonessential Yeast Genes Establishes Platforms for Testing Inhibitors of Human Proteins

“…The simplicity and genetic tractability of the budding yeast, Saccharomyces cerevisiae, make it a model experimental system to delineate conserved biological pathways and processes such as those involved in CIN (Measday and Stirling 2016). Large-scale yeast screens have generated a comprehensive list of genes whose mutation (Myung et al 2001;Smith et al 2004;Kanellis et al 2007;Yuen et al 2007;Andersen et al 2008;Stirling et al 2011) or overexpression (Zhu et al 2015;Ang et al 2016;Duffy et al 2016;Frumkin et al 2016;Tutaj et al 2019) contribute to CIN. Yeast can also be utilized to identify chemical sensitivities to cytotoxic agents caused by CIN gene mutations that may be exploited to selectively target tumor cells (O'Neil et al 2017).…”