Hsp90 modulates CAG repeat instability in human cells.

TitleHsp90 modulates CAG repeat instability in human cells.
Publication TypeJournal Article
Year of Publication2010
AuthorsMittelman, D, Sykoudis, K, Hersh, M, Lin, Y, Wilson, JH
JournalCell Stress Chaperones
Volume15
Issue5
Pagination753-9
Date Published2010 Sep
ISSN1466-1268
KeywordsCell Line, HSP90 Heat-Shock Proteins, Humans, Immunoblotting, Microsatellite Instability, Rad51 Recombinase, RNA, Small Interfering, Trinucleotide Repeats
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.

DOI10.1007/s12192-010-0191-0
Alternate JournalCell Stress Chaperones
PubMed ID20373063
PubMed Central IDPMC3006633
Grant ListGM38219 / GM / NIGMS NIH HHS / United States
F32 NS064762 / NS / NINDS NIH HHS / United States
R01 GM038219 / GM / NIGMS NIH HHS / United States
F32 EY007001 / EY / NEI NIH HHS / United States
T32 DK007696 / DK / NIDDK NIH HHS / United States
T32 EY007001 / EY / NEI NIH HHS / United States
EY07001 / EY / NEI NIH HHS / United States
NS064762 / NS / NINDS NIH HHS / United States
DK007696 / DK / NIDDK NIH HHS / United States