Mutations in histones dysregulate copper homeostasis leading to defect in Sec61 dependent protein translocation mechanism in Saccharomyces cerevisiae.

The translocation of proteins from the cytoplasm to the endoplasmic reticulum occurs via a conserved Sec61 protein channel. Previously, we reported that mutations in histones cause downregulation of a CUP1 copper metallothionein and copper exposure inhibits the activity of Sec61. However, the role of epigenetic dysregulation on the activity of channel is not clear.

Mechanisms of DNA methylation and histone modifications.

The field of genetics has expanded a lot in the past few decades due to the accessibility of human genome sequences, but still, the regulation of transcription cannot be explicated exclusively by the sequence of DNA of an individual. The coordination and crosstalk between chromatin factors which are conserved is indispensable for all living creatures. The regulation of gene expression has been dependent on the methylation of DNA, post-translational modifications of histones, effector proteins, chromatin remodeler enzymes that affect the chromatin structure and function, and other cellular activities such as DNA replication, DNA repair, proliferation and growth.

Copper inhibits protein maturation in the secretory pathway by targeting the Sec61 translocon in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, proteins destined for secretion utilize the post-translational translocon machinery to gain entry into the endoplasmic reticulum. These proteins then mature by undergoing a number of post-translational modifications in different compartments of the secretory pathway. While these modifications have been well established for many proteins, to date only a few studies have been conducted regarding the conditions and factors affecting maturation of these proteins before entering into the endoplasmic reticulum.

Heavy metal exposure induces Yap1 and Hac1 mediated derepression of GSH1 and KAR2 by Tup1-Cyc8 complex.

Heavy metal pollution is one of the most severe environmental problem. The toxicity of heavy metals is correlated with the production of increased reactive oxygen species and misfolded protein accumulation. Exposures of these metals even at low concentrations adversely affect human health.

The ATP-dependent SWI/SNF and RSC chromatin remodelers cooperatively induce unfolded protein response genes during endoplasmic reticulum stress.

The SWI/SNF subfamily remodelers (SWI/SNF and RSC) generally promote gene expression by displacing or evicting nucleosomes at the promoter regions. Their action creates a nucleosome-depleted region where transcription machinery accesses the DNA. Their function has been shown critical for inducing stress-responsive transcription programs.

ABC transporter Pdr5 is required for cantharidin resistance in Saccharomyces cerevisiae.

Cantharidin is a potent anti-cancer drug and is known to exert its cytotoxic effects in several cancer cell lines. Although we have ample knowledge about its mode of action, we still know a little about cantharidin associated drug resistance mechanisms which dictates the efficacy and cytotoxic potential of this drug. In this direction, in the present study we employed Sacharomyces cerevisiae as a model organism and screened mutants of pleiotropic drug resistance network of genes for their susceptibility to cantharidin.

The mechanisms of action of chromatin remodelers and implications in development and disease.

The eukaryotic genetic material is packaged in the form of chromatin by wrapping DNA around nucleosomes. Cells maintain chromatin in a dynamic state by utilising various ATP-dependent chromatin remodelling complexes which can induce structural transformations in the chromatin. All chromatin remodelers contain an ATP hydrolysing-DNA translocase motor which facilitates nucleosomal DNA translocation.

Modulation of ruthenium anticancer drugs analogs with tolfenamic acid: Reactivity, biological interactions and growth inhibition of yeast cell.

We synthesized two ruthenium(II) complexes: trans,trans-[Ru(im)(tfa)] (1) and trans,trans‑[Ru(in)(tfa)] (2) where im = 1H‑imidazole, in = 1H‑indazole and tfa = tolfenamic acid, a potential nonsteroidal anti-inflammatory drug (NSAID). The NSAID was opted as bioactive ligand to understand its synergistic therapeutic effect in structurally analogous Ru(II)-compounds with KP418 (imidazolium trans‑[tetrachloridobis(1H‑imidazole)ruthenate(III)]) and KP1019 (indazolium trans‑[tetrachloridobis(1H‑indazole)ruthenate(III)]). The complexes were studied using various analytical methods and structure was determined by X-ray crystallography.

Zinc oxide nanoparticles induce toxicity by affecting cell wall integrity pathway, mitochondrial function and lipid homeostasis in Saccharomyces cerevisiae.

Growing numbers of nanotoxicity research demonstrating that mechanical damage and oxidative stress are potential modes of nanoparticles (NPs) induced toxicity. However, the underlying mechanisms by which NPs interact with the eukaryotic cell and affect their physiological and metabolic functions are not fully known. We investigated the toxic effects of zinc oxide nanoparticles (ZnO-NPs) on budding yeast, Saccharomyces cerevisiae and elucidated the underlying mechanism.

Modifying Chromatin by Histone Tail Clipping.

Post-translational modifications (PTMs) of histone proteins play a crucial role in the regulation of chromatin structure and functions. Studies in the last few decades have revealed the significance of histone PTMs in key cellular processes including DNA replication, repair, transcription, apoptosis and cell cycle regulation. The PTMs on histones are carried out by chromatin modifiers, which are reversible in nature.

Efficient expression and purification of biologically active human cystatin proteins.

Cystatins are reversible cysteine protease inhibitor proteins. They are known to play important roles in controlling cathepsins, neurodegenerative disease, and in immune system regulation. Production of recombinant cystatin proteins is important for biochemical and function characterization.

Flocculation in Saccharomyces cerevisiae is regulated by RNA/DNA helicase Sen1p.

The Nrd1-Nab3-Sen1 (NNS) complex terminates transcription of non-coding RNA genes and mediates degradation of the produced transcript by the nuclear exosome. The NNS complex also represses some stress response genes, by stimulating premature termination. A well-characterized stress response in yeast is flocculation, where cells aggregate to form flocs under expression of lectin-encoding genes designated as FLOs.

The transcription factor Rap1p is required for tolerance to cell-wall perturbing agents and for cell-wall maintenance in Saccharomyces cerevisiae.

Yeast repressor activator protein (Rap1p) is involved in genomic stability and transcriptional regulation. We explored the function of Rap1p in yeast physiology using Rap1p truncation mutants. Our results revealed that the N-terminal truncation of Rap1p (Rap1ΔN) leads to hypersensitivity towards elevated temperature and cell-wall perturbing agents.

Anti-cancer drug KP1019 induces Hog1 phosphorylation and protein ubiquitylation in Saccharomyces cerevisiae.

Ruthenium-based anti-cancer drugs have attracted increasing interest in the last 20 years. KP1019 is one of the ruthenium-containing compounds that has demonstrated anti-tumor activity against various cancers, and has been tested in several clinical trials. Despite its success, the mode of action of KP1019 is not well described.

Anti-cancer drug KP1019 modulates epigenetics and induces DNA damage response in Saccharomyces cerevisiae.

KP1019 comprises a class of ruthenium compounds having promising anticancer activity. Here, we investigated the molecular targets of KP1019 using Saccharomyces cerevisiae as a model organism. Our results revealed that in the absence of the N-terminal tail of histone H3, the growth inhibitory effect of KP1019 was markedly enhanced.