Both the Charged Linker Region and ATPase Domain of Hsp90 Are Essential for Rad51-Dependent DNA Repair

Abstract

The inhibition of Hsp90 in cancerous cells has been correlated with the reduction in double-strand break (DSB repair) activity. However, the precise effect of Hsp90 on the DSB repair pathway in normal cells has remained enigmatic. Our results show that the Hsp82 chaperone, the ortholog of mammalian Hsp90, is indispensable for homologous-recombination (

Synergistic Antiproliferative Activity of the RAD51 Inhibitor IBR2 with Inhibitors of Receptor Tyrosine Kinases and Microtubule Protein

“…In K562 cells (mutant c-Kit and Bcr-Abl expression), IBR2 enhanced regorafenib, which targets c-Kit. c-Kit and RAD51 are both client proteins of heat shock protein 90 (Hsp90), as are Bcr-Abl, Akt, and BRCA1 (Noguchi et al, 2006;Smyth et al, 2012;Suhane et al, 2015;Jiang et al, 2017). In Kasumi-1 cells (normal Abl and mutant c-Kit), which are hypersensitive to imatinib and regorafenib ( Fig.…”

“…8. Bcr-Abl upregulates RAD51 (Slupianek et al, 2001;Noguchi et al, 2006;Suhane et al, 2015;Jiang et al, 2017). Therefore, in a cell line such as K562 which is dependent on Bcr-Abl as its oncogenic driver, the Bcr-Abl inhibitor imatinib could potentially cause a decrease in RAD51, increasing sensitivity to IBR2.…”

“…11. For the following reasons, Hsp90 was considered as a possible secondary target for IBR2: 1) inhibition of Hsp90 (A549 and H1975) or its yeast ortholog heat shock protein 82 results in decreased RAD51 (degradation by proteosomes) and inhibits DNA repair (Ko et al, 2012;Segawa et al, 2014;Suhane et al, 2015); 2) the Hsp90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) downregulated Bcr-Abl protein level in CML cells, and acted synergistically with imatinib to kill Bcr-Abl-overexpressing CML cells (Radujkovic et al, 2005); 3) Hsp90 is a chaperone for EGFR and Bcr-Abl (Jhaveri et al, 2014); and 4) inhibition of Hsp90 sensitizes human lung Fig. 7.…”

The Nuclear and DNA-Associated Molecular Chaperone Network

“…Mutations in SSL2, when combined with HSP82 and HSC82 mutant alleles lead to synthetic growth defects (Flom et al 2005). Hsp90 could stabilize several DNA repair proteins as exemplified by Rad51, ATM, NBN, and XRCC1 (Fang et al 2014;Suhane et al 2015;Pennisi et al 2017), and/or could regulate the dynamics of the DNA repair process. However, the complete mechanism behind Hsp90 action during DNA repair has not yet been elucidated.…”

Cancer Chemoprevention Effects of Geldanamycin and 17-AAG in Human Oral Squamous Cell Carcinoma

“…While treatment with HSP90 inhibitors increased apoptotic effect, it has yet to be revealed whether such effects are the necessary and sufficient condition for anticancer activity of HSP90 inhibitors [27].Since G2 arrest was induced after treatment of oral cancer cell lines with HSP90 inhibitors in this study, it should be further studied on G2 arrest related cyclin and CDK expression. In addition, since G2 arrest is related with DNA damage, it is required to study on DNA damage caused by treatment with HSP90 inhibitor[20][21][22][23][24][25].Clinical development of HSP90 inhibitors has been rapidly progressed for application to chemotherapy for cancer. To date, the principle for 17-AAG has been proven through various steps of phase I clinical trial, and phase II clinical trial for 17-AAG has been initiated by the support of the NCI (National Cancer Institute).…”