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ACS Synth Biol

Title:		Introduction of Premature Stop Codons as an Evolutionary Strategy To Rescue Signaling Network Function
Author(s):		Kompella PS; Moses AM; Peisajovich SG;
Address:		"Department of Cell and Systems Biology, University of Toronto 25 Harbord Street, Toronto, Ontario M5S 3G5, Canada"
Journal Title:		ACS Synth Biol
Year:		2017
Volume:		20161227
Issue:		3
Page Number:		446 - 454
DOI:		10.1021/acssynbio.6b00142
ISSN/ISBN:		2161-5063 (Electronic) 2161-5063 (Linking)
Abstract:		"The cellular concentrations of key components of signaling networks are tightly regulated, as deviations from their optimal ranges can have negative effects on signaling function. For example, overexpression of the yeast mating pathway mitogen-activated protein kinase (MAPK) Fus3 decreases pathway output, in part by sequestering individual components away from functional multiprotein complexes. Using a synthetic biology approach, we investigated potential mechanisms by which selection could compensate for a decrease in signaling activity caused by overexpression of Fus3. We overexpressed a library of random mutants of Fus3 and used cell sorting to select variants that rescued mating pathway activity. Our results uncovered that one remarkable way in which selection can compensate for protein overexpression is by introducing premature stop codons at permitted positions. Because of the low efficiency with which premature stop codons are read through, the resulting cellular concentration of active Fus3 returns to values within the range required for proper signaling. Our results underscore the importance of interpreting genotypic variation at the systems rather than at the individual gene level, as mutations can have opposite effects on protein and network function"
Keywords:		"Codon, Terminator/*genetics Fungal Proteins/genetics Genotype Mating Factor/genetics Mitogen-Activated Protein Kinases/*genetics Mutation/genetics Signal Transduction/*genetics Synthetic Biology/methods Yeasts/genetics evolution premature stop codon signa;"
Notes:		"MedlineKompella, Purnima S Moses, Alan M Peisajovich, Sergio G eng Research Support, Non-U.S. Gov't 2016/12/10 ACS Synth Biol. 2017 Mar 17; 6(3):446-454. doi: 10.1021/acssynbio.6b00142. Epub 2016 Dec 27"