PT  - JOURNAL ARTICLE
AU  - Toshiki Kijima
AU  - Thomas L. Prince
AU  - Megan L. Tigue
AU  - Kendrick H. Yim
AU  - Harvey Schwartz
AU  - Kristin Beebe
AU  - Sunmin Lee
AU  - Marek A. Budzynski
AU  - Heinric Williams
AU  - Jane B. Trepel
AU  - Lea Sistonen
AU  - Stuart Calderwood
AU  - Len Neckers
TI  - HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation
AID  - 10.1101/207001
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 207001
4099  - http://biorxiv.org/content/early/2018/03/02/207001.short
4100  - http://biorxiv.org/content/early/2018/03/02/207001.full
AB  - Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.