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Originally published as Genetics Published Articles Ahead of Print on July 18, 2006.
Genetics, Vol. 174, 937-944, October 2006, Copyright © 2006
doi:10.1534/genetics.106.061564
Why Molecular Chaperones Buffer Mutational Damage: A Case Study With a Yeast Hsp40/70 System
Joanna Bobula*,1,
Katarzyna Tomala*,1,
Elzbieta Jez*,
Dominika M. Wloch*,
Rhona H. Borts
and
Ryszard Korona*,2
* Institute of Environmental Sciences, Jagiellonian University, 30-387 Krakow, Poland and Department of Genetics, University of Leicester, Leicester LE7 1RH, United Kingdom
2 Corresponding author: Institute of Environmental Sciences, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
E-mail: korona{at}eko.uj.edu.pl
The malfunctioning of molecular chaperones may result in uncovering genetic variation. The molecular basis of this phenomenon remains largely unknown. Chaperones rescue proteins unfolded by environmental stresses and therefore they might also help to stabilize mutated proteins and thus mask damages. To test this hypothesis, we carried out a genomewide mutagenesis followed by a screen for mutations that were synthetically harmful when the RAC–Ssb1/2 cytosolic chaperones were inactive. Mutants with such a phenotype were found and mapped to single nucleotide substitutions. However, neither the genes identified nor the nature of genetic lesions implied that folding of the mutated proteins was being supported by the chaperones. In a second screen, we identified temperature-sensitive (ts) mutants, a phenotype indicative of structural instability of proteins. We tested these for an association with sensitivity to loss of chaperone activity but found no such correlation as might have been expected if the chaperones assisted the folding of mutant proteins. Thus, molecular chaperones can mask the negative effects of mutations but the mechanism of such buffering need not be direct. A plausible role of chaperones is to stabilize genetic networks, thus making them more tolerant to malfunctioning of their constituents.
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Genetics 2006 174: NP.