H3K9 methylation (H3K9me) specifies the establishment and maintenance of transcriptionally silent epigenetic states or heterochromatin. The enzymatic erasure of histone modifications is widely assumed to be the primary mechanism that reverses epigenetic silencing. Here, we reveal an inversion of this paradigm where a putative histone demethylase Epe1 in fission yeast, has a non-enzymatic function that opposes heterochromatin assembly. Mutations within the putative catalytic JmjC domain of Epe1 disrupt its interaction with Swi6HP1 suggesting that this domain might have other functions besides enzymatic activity. The C-terminus of Epe1 directly interacts with Swi6HP1, and H3K9 methylation stimulates this protein-protein interaction in vitro and in vivo. Expressing the Epe1 C-terminus is sufficient to disrupt heterochromatin by outcompeting the histone deacetylase, Clr3 from sites of heterochromatin formation. Our results underscore how histone modifying proteins that resemble enzymes have non-catalytic functions that regulate the assembly of epigenetic complexes in cells.

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 (TF). 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 TFs in response to various physiological cues. Second, 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. Third, 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.

The molecular mechanism behind hyperthermia coupled to radiation-induced DNA damage sensitivity is not known. The model organism Saccharomyces cerevisiae is used to establish that a transient heat shock and particularly the concomitant induction of Hsp90 lead to increased genomic instability via transcriptional regulation of the major checkpoint kinase Rad53.

Recently, Hsp90 functional loss has been linked to aneuploidy; however, until now none of the components of sister chromatid cohesion (SCC) have been demonstrated as the putative clients of Hsp90. In this study, we have established that Chl1, the protein which is involved in maintaining sister chromatid cohesion as well as in preventing chromosome loss, is a direct client of Hsp90. Thus, with understanding of the molecular mechanism, how Hsp90 controls the cohesion machinery might reveal new insights which can be exploited further for attenuation of tumorigenesis.

No abstract