Abstract
Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and DNA repair. Cells respond to DNA damage by activating complex DNA damage response (DDR) pathways that include: (i) cell cycle arrest; (ii) transcriptional and post-translational activation of a subset of genes, including those associated with DNA repair; and (iii) triggering of programmed cell death. The efficacy of the DDR pathways is influenced by the nuclear levels of DNA repair proteins, which are regulated by balancing between protein synthesis and degradation as well as by nuclear import and export. The inability to respond properly to either DNA damage or to DNA repair leads to genetic instability, which in turn may enhance the rate of cancer development. Multiple components of the DNA double strand breaks repair machinery, including BRCA1, BRCA2, CHK1, DNA-PKcs, FANCA, and the MRE11/RAD50/NBN complex, have been described to be client proteins of Hsp90, which acts as a regulator of the diverse DDR pathways. Inhibition of Hsp90 actions leads to the altered localization and stabilization of DDR proteins after DNA damage and may represent a cell-specific and tumor-selective radiosensibilizer. Here, the role of Hsp90-dependent molecular mechanisms involved in cancer onset and in the maintenance of the genome integrity is discussed and highlighted.
Highlights
Cellular protein homeostasis, termed proteostasis, regulates protein folding and functions in order to maintain the well-being condition of both the cells and the organism; protein misfolding and unfolding are associated to several human disease [1]
Cells respond to DNA damage by activating the complex DNA damage response (DDR) pathway that includes the cell cycle arrest, the transcriptional and post-translational activation of a subset of genes including those associated with DNA repair, and, under some circumstances, the triggering of programmed cell death
The active forms of FANCD2 and FANCI localize to the chromatin at sites of DNA damage, where they interact with DNA repair proteins including BRCA1 and BRCA2
Summary
Termed proteostasis, regulates protein folding and functions in order to maintain the well-being condition of both the cells and the organism; protein misfolding and unfolding are associated to several human disease [1]. Hsp is one of the most abundant and conserved molecular chaperones playing an essential role in eukaryotic cells proteostasis. To ensure the proper protein assembly, the Hsp chaperone machinery performs three main functions under normal conditions: (i) it interacts with a vast array of clients through adapter co-chaperones (e.g., p23 and Cdc37); (ii) it stabilizes specific folding intermediates that allows clients to interact with specific binding partners; and (iii) it regulates the ubiquitin-mediated proteasome degradation [2,10,11,12,14,15]. Cdc, playing a pivotal role in cell cycle regulation, p23, being a major player in the DNA repair processes, and Aha, activating the Hsp ATPase activity [18,19]. Inhibition of the ATPase activity of Hsp impairs client protein recognition, causing clients degradation [10,26,27]
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