In the last decade Hsp90 has emerged as a major regulator of cancer cell growth and proliferation In cancer cells, it assists in giving maturation to oncogenic proteins including several kinases and transcription factors Recent studies have shown that apart from its chaperone activity, it also imparts regulation of transcription machinery and thereby alters the cellular physiology Hsp90 and its co-chaperones modulate transcription at-least at three different levels In the first place, they alter the steady-state levels of certain transcription factors in response to various physiological cues Secondly, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment Thirdly, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression In this review, we discuss the role of Hsp90 in all the three aforementioned mechanisms of transcriptional control, taking examples from various model organisms with a special emphasis on cancer progression

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Hsp90, the concertmaster: tuning transcription.

National Institutes of Health (U.S.). Genomics Based Drug Discovery-Driving Medical Project (Grant UL1-DE019585)

Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition

Saccharomyces cerevisiae (budding yeast) and Schizosaccharomyces pombe (fission yeast) are two of the most recognised and well-studied model systems for epigenetic regulation and the inheritance of chromatin states. Their silent loci serve as a proxy for heterochromatic chromatin in higher eukaryotes, and as such both species have provided a wealth of information on the mechanisms behind the establishment and maintenance of epigenetic states, not only in yeast, but in higher eukaryotes. This review focuses specifically on the role of histone modifications in governing telomeric silencing in S. cerevisiae and centromeric silencing in S. pombe as examples of genetic loci that exemplify epigenetic inheritance. We discuss the recent advancements that for the first time provide a mechanistic understanding of how heterochromatin, dictated by histone modifications specifically, is preserved during S-phase. We also discuss the current state of our understanding of yeast nucleosome dynamics during DNA replication, an essential component in delineating the contribution of histone modifications to epigenetic inheritance.

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Yeast epigenetics: the inheritance of histone modification states.

It is well documented that elevated body temperature causes tumors to regress upon radiotherapy. However, how hyperthermia induces DNA damage sensitivity is not clear. We show that a transient heat shock and particularly the concomitant induction of Hsp90 lead to increased genomic instability under DNA-damaging conditions. Using Saccharomyces cerevisiae as a model eukaryote, we demonstrate that elevated levels of Hsp90 attenuate efficient DNA damage signaling and dictate preferential use of the potentially mutagenic double-strand break repair pathway. We show that under normal physiological conditions, Hsp90 negatively regulates RAD53 transcription to suppress DNA damage checkpoint activation. However, under DNA damaging conditions, RAD53 is derepressed, and the increased level of Rad53p triggers an efficient DNA damage response. A higher abundance of Hsp90 causes increased transcriptional repression on RAD53 in a dose-dependent manner, which could not be fully derepressed even in the presence of DNA damage. Accordingly, cells behave like a rad53 loss-of-function mutant and show reduced NHEJ efficiency, with a drastic failure to up-regulate RAD51 expression and manifestly faster accumulation of CLN1 and CLN2 in DNA-damaged G1, cells leading to premature release from checkpoint arrest. We further demonstrate that Rad53 overexpression is able to rescue all of the aforementioned deleterious effects caused by Hsp90 overproduction.

Hsp90 induces increased genomic instability toward DNA-damaging agents by tuning down RAD53 transcription.

Double strand breaks may be a missing link between entropy and aging.

The epigenetic writer Sir2 maintains the heterochromatin state of chromosome in three chromosomal regions, namely, the silent mating type loci, telomeres, and the ribosomal DNA (rDNA). In this study, we demonstrated the mechanism by which Sir2 is regulated under heat stress. Our study reveals that a transient heat shock causes a drastic reduction in the SIR2 transcript which results in sustained failure to initiate silencing for as long as 90 generations. Hsp82 overexpression, which is the usual outcome of heat shock treatment, leads to a similar downregulation of SIR2 transcription. Using a series of genetic experiments, we have established that heat shock or Hsp82 overexpression causes upregulation of CUP9 that, in turn, represses SIR2 transcription by binding to its upstream activator sequence. We have mapped the cis regulatory element of SIR2. Our study shows that the deletion of cup9 causes reversal of the Hsp82 overexpression phenotype and upregulation of SIR2 expression in heat-induced Hsp82-overexpressing cells. On the other hand, we found that Cup9 overexpression represses SIR2 transcription and leads to a failure in the establishment of heterochromatin. The results of our study highlight the mechanism by which environmental factors amend the epigenetic configuration of chromatin.

Heat stress induced Cup9 dependent transcriptional regulation of Sir2


 Combination drug treatments are frequently used in many diseases, including cancers and AIDS. The main aims of these treatments are to reduce toxicity and improve drug efficacy by inhibiting the activity of a specific target or groups of targets in a cell. The net effect of combination drug efficacy is mainly quantified and interpreted by various terminologies like synergy, additive, agonism, and antagonism based on drugs dose ratio. In single or combination drug treatment, drug action occurs on cells due to the intermolecular level interaction of drugs with protein/DNA/RNA/Enzyme. This type of inter-molecular level interaction can be detected with the help of docking software. However, in the case of combination drug treatments, it is very challenging to identify the multiple drug interaction on each protein with docking score and binding energy. So the proposed work does not follow the classical approach of docking study to predicting the result based on docking score and binding energy. Here we consider drug properties and complex energy of the multiple drug binded complexes for predicting the result. Based on this study, we identified the intermolecular level interaction of synergistic effect showed drugs Crizotinib and Temozolomide in C-MET, C-ROS1, and ALK targets of Glioblastoma Multiforme(GBM) and identified the most stable drug complexes by MD simulation.

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Identification of Combination Drug Interaction With Selected Targets of Globlastoma Multiforme Based on Drug Properties and Complex Energy of Docked Complex: a New Approach in Docking Study

Sheeba K

Papers

Heat stress induced Cup9 dependent transcriptional regulation of Sir2

Identification of Combination Drug Interaction With Selected Targets of Globlastoma Multiforme Based on Drug Properties and Complex Energy of Docked Complex: a New Approach in Docking Study