title: Hsp90 modulates CAG repeat instability in human cells.
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.
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mittelman
authors.forename: Kristen
authors.initials: K
authors.lastname: Sykoudis
authors.forename: Megan
authors.initials: M
authors.lastname: Hersh
authors.forename: Yunfu
authors.initials: Y
authors.lastname: Lin
authors.forename: John H
authors.initials: JH
authors.lastname: Wilson
mesh_terms: D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D053842:Microsatellite Instability; D034741:RNA, Small Interfering; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D034741:RNA, Small Interfering; C495153:RAD51 protein, human; D051135:Rad51 Recombinase