Disruption of Heat-shock Proteins Allows Drug Resistance Acquisition in Fungi

Heat-shock proteins (Hsp’s) are an essential part of a cells defence against many different environmental stresses. However, an article by Pigluicci suggests that they can also act as a genetic buffer, protecting the organism by preventing the expression of mutations in the genome.

The article by Cowen and Lindquist shows that fungi can acquire drug resistance after Hsp’s are disrupted. In many cases this was due to the drug’s target protein being denatured by environmental stress and the Hsp not refolding it correctly, causing the drug not to recognize and bind the protein. However, in some cases the acquisition of drug resistance was due to genetic variation which had previously been prevented from being expressed by the Hsp’s. Cowen and Lindquist concluded that Hsp’s have the capacity to buffer the expression of genetic and epigenetic variation and to release it in response to environmental stress.

However, although this acquisition of drug resistance should increase an organism’s fitness to survive, the disruption of the Hsp’s will most likely also cause other important proteins, for example proteins necessary for metabolism, to fold incorrectly and lose function.

References
Primary Reference – Cowen, L. and Lindquist, S. (30 Sep, 2005) Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science Vol. 309. 2185-2189.

Secondary Reference – Pigluicci, M (6 June, 2002) Buffer Zone. Nature. Vol. 417. 598-599

Written by: 41177811
Topic: Directed Mutations (Heat-shock Proteins)

Hsp90 many not be the sole perpetrator in buffering genetic change

Over the last decade, there has been growing evidence (cited by Pigliucci, 2002) that Hsp90, traditionally thought of as a capacitor for environmental change, may be able to canalise genetic change (mutations) as well. Early research in this area investigated the effects of inhibition of Hsp90 on qualitative and discrete quantitative traits in various organisms.

Recently, however, Debat, et. al. have investigated the role of Hsp90 in genetic canalisation of a more complex quantitative trait, wing shape of D. Melanogaster. Hsp90 activity was inhibited in three different experiments; by adding geldanamycin (a known Hsp90 inhibitor) to diets, by the addition of Hsp83 (the gene encoding Hsp90) mutant chromosomes into fly genomes, and by introgression of a specific Hsp83 mutant allele into the fly genome.

Wing shape was measured using the complex methods of “geometric morphometrics”, and their results were very surprising - no increase in phenotypic variation was observed when Hsp90 was inhibited in geldanamycin and mutant chromosome experiments, but an increase was observed in the introgression experiment.

These mixed results led the authors to propose that Hsp90 might not play as central a role in genetic canalisation as initially thought, and may simply be playing a small part in a more complex,as-yet undefined system.

Clearly, the scientific community is at a very young stage in the understanding of the role of Hsp90 in masking genetic variation. Further research can perhaps shed some more light on the issue, and could particularly focuse on the mechanism of genetic canalisation of Hsp90.

References

Pigliucci, M. (2002). Buffer Zone. Nature, vol 417, p598-99)

Debat, V., et.al. (2006) Hsp90 and the quantitative variation of wing shape in D. melanogaster. Evolution, 60 (12): 2529-2538

Written by: Student Number 40974077