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Feb 12, 2009

Function of Mutant Gene Restored in Yeast Model

  • Researchers at Fox Chase Cancer Center report that they were able to restore the function of a mutant gene in a yeast model of disease by manipulating the available amounts of protein Hsp70, which helps amino acid chains fold into their proper protein form.

    Hsp70 works in equilibrium with another heat shock protein, Hsp26, as a sort of biochemical damage control system, the scientists explain. While Hsp70 acts like a chaperone to restore the function of such proteins, Hsp26 targets the misfolded proteins to the proteosome.

    Since the two proteins seem to function in opposition—competing to clean up damaged proteins within cells—the investigators removed the gene encoding Hsp26 from yeast and saw a nine-fold increase in the amount of properly functioning human cystathionine beta-synthase (CBS) protein. CBS deficiency is an inherited metabolic disorder that was used as a genetic model.

    “If we can target Hsp26 and take it out of circulation, we might be able to give Hsp70 more room to operate,” explains Warren Kruger, Ph.D., senior faculty member at Fox Chase.

    Previous experiments showed that exposure to alcohol restored the function of a mutant human CBS protein expressed in genetically engineered yeast cells. This exposure activates heat shock proteins like Hsp70 that help the cell respond to the damage from stress. The sudden excess of Hsp70 had the side effect of rescuing mutated proteins in addition to those damaged by alcohol.

    “Hsp70 pulls a misfolded amino acid chain apart like a twisted rubber band and allows it to snap back into place, which we found can restore a significant percentage of proteins to working shape,” says Dr. Kruger. “If this can be done in humans, it could represent a way of reducing the severity or perhaps correcting certain hereditary diseases, even some familial cancers.”

    While the study was done in a yeast model for human disease, humans possess at least nine members of the Hsp70 family of chaperones. Dr. Kruger and his colleagues are currently studying how to adapt these findings to human disease. “The more chances we give Hsp70 proteins to try to fix the output of mutant genes, the more chances are that they will succeed.”

    The study appears in the current online issue of the Journal of Biological Chemistry.

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