Cell Stress and Chaperones

, Volume 15, Issue 5, pp 753–759 | Cite as

Hsp90 modulates CAG repeat instability in human cells

  • David Mittelman
  • Kristen Sykoudis
  • Megan Hersh
  • Yunfu Lin
  • John H. Wilson
Short Communication

Abstract

The Hsp90 molecular chaperone has been implicated as a contributor to evolution in several organisms by revealing cryptic variation that can yield dramatic phenotypes when the chaperone is diverted from its normal functions by environmental stress. In addition, as a cancer drug target, Hsp90 inhibition has been documented to sensitize cells to DNA-damaging agents, suggesting a function for Hsp90 in DNA repair. Here we explore the potential role of Hsp90 in modulating the stability of nucleotide repeats, which in a number of species, including humans, exert subtle and quantitative consequences for protein function, morphological and behavioral traits, and disease. We report that impairment of Hsp90 in human cells induces contractions of CAG repeat tracks by tenfold. Inhibition of the recombinase Rad51, a downstream target of Hsp90, induces a comparable increase in repeat instability, suggesting that Hsp90-enabled homologous recombination normally functions to stabilize CAG repeat tracts. By contrast, Hsp90 inhibition does not increase the rate of gene-inactivating point mutations. The capacity of Hsp90 to modulate repeat-tract lengths suggests that the chaperone, in addition to exposing cryptic variation, might facilitate the expression of new phenotypes through induction of novel genetic variation.

Keywords

Hsp90 chaperone Stress-induced mutation Repeat instability Homologous recombination 

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Copyright information

© Cell Stress Society International 2010

Authors and Affiliations

  • David Mittelman
    • 1
    • 2
  • Kristen Sykoudis
    • 3
  • Megan Hersh
    • 3
  • Yunfu Lin
    • 3
  • John H. Wilson
    • 2
    • 3
  1. 1.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA
  2. 2.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  3. 3.Verna and Marrs McLean Department of Biochemistry and Molecular BiologyBaylor College of MedicineHoustonUSA

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