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Hsp90 modulates CAG repeat instability in human cells

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Cell Stress and Chaperones Aims and scope

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.

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Acknowledgments

We would like to thank Dr. John W. Fondon III and Dr. Steve W. Lockless for insightful discussions and manuscript suggestions. We also would like to thank Drs. Jason Shohet and Zaowen Chen for technical assistance with real-time RT-PCR measurements. In addition, we thank the members of the Wilson laboratory for helpful suggestions and critical comments. This work was supported by a T-32 grant from the National Institutes of Health (EY07001) to D.M., an F-32 grant from the National Institutes of Health (NS064762) to D.M., a National Institute of Diabetes and Digestive and Kidney Diseases training grant (DK007696) to K.S., and an R01 grant from the National Institutes of Health (GM38219) to J.H.W.

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Authors and Affiliations

  1. Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    David Mittelman

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    David Mittelman & John H. Wilson

  3. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Kristen Sykoudis, Megan Hersh, Yunfu Lin & John H. Wilson

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  1. David Mittelman
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  5. John H. Wilson
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Correspondence to John H. Wilson.

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Mittelman, D., Sykoudis, K., Hersh, M. et al. Hsp90 modulates CAG repeat instability in human cells. Cell Stress and Chaperones 15, 753–759 (2010). https://doi.org/10.1007/s12192-010-0191-0

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  • DOI: https://doi.org/10.1007/s12192-010-0191-0

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