Solar ultraviolet radiation (UVR) suppresses skin immunity, which facilitates initiation of lesions and establishment tumors by promoting immune evasion. It is unclear whether checkpoints are involved in the modulation immunity UVR. Here, we report that UVR exposure significantly increased expression checkpoint molecule PD-L1 melanoma cells. The damage-associated molecular patterns HMGB1 was secreted melanocytes keratinocytes upon UVR, subsequently activated receptor for advanced glycation...

Epigenetic changes in chromatin through histone post-translational modifications are essential for altering gene transcription response to environmental cues. How regulated by stimuli remains poorly understood yet this process is critical delineating how epigenetic pathways influenced the cellular environment. We have used target of rapamycin (TOR) pathway, which transmits nutrient signals control cell growth, as a model delineate mechanisms underlying phenomenon. A chemical genomics screen...

The proteasome regulates histone lysine methylation and gene transcription, but how it does so is poorly understood. To better understand this process, we used the epistatic miniarray profile (E-MAP) approach to identify factors that genetically interact with proteasomal subunits. In addition members of Set1 complex mediate H3 4 (H3K4me), found deleting CCR4/NOT mRNA processing exhibit synthetic phenotypes when combined mutants. Further biochemical analyses revealed physical associations...

Background The Ccr4-Not complex is a key eukaryotic regulator of gene transcription and cytoplasmic mRNA degradation. Whether this also affects aspects post-transcriptional regulation, such as export, remains largely unexplored. Human Caf1 (hCaf1), member, interacts with regulates the arginine methyltransferase PRMT1, whose targets include RNA binding proteins involved in export. However, functional significance regulation poorly understood. Methodology/Principal Findings Here we demonstrate...

Ribosomal RNA synthesis is controlled by nutrient signaling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. mTORC1 regulates ribosomal expression affecting Polymerase I (Pol I)-dependent transcription DNA (rDNA) but mechanisms involved remain obscure. This study provides evidence that Ccr4-Not complex, which II II) transcription, also functions downstream to control Pol activity. localizes rDNA and physically associates with holoenzyme while disruption perturbs...

In yeast and other eukaryotes, the histone methyltransferase Set1 mediates methylation of lysine 4 on H3 (H3K4me). This modification marks 5' end transcribed genes in a 5'-to-3' tri- to di- monomethyl gradient promotes association chromatin-remodeling histone-modifying enzymes. Here we show that Ctk1, serine 2 C-terminal domain (CTD) kinase for RNA polymerase II (RNAP II), regulates H3K4 methylation. We found CTK1 deletion nearly abolished monomethylation yet caused significant increase...

Non-coding RNAs (ncRNAs) play critical roles in gene regulation. In eukaryotic cells, ncRNAs are processed and/or degraded by the nuclear exosome, a ribonuclease complex containing catalytic subunits Dis3 and Rrp6. The TRAMP (Trf4/5-Air1/2-Mtr4 polyadenylation) is exosome cofactor budding yeast that stimulates to process/degrade human components have recently been identified. Importantly, mutations genes cause neurodegenerative disease. How interacts with other cofactors orchestrate...

Abstract Altering chromatin structure by blocking histone deacetylase activity with specific inhibitors such as trichostatin A can result in an up-regulation of gene expression. In this report, however, we show that expression the ETS domain transcription factor PU.1 is down-regulated cells following addition A. The loss seen at both mRNA and protein levels multiple cell lines reversible removal drug. More importantly, results a target expression, including CD11b, c-fms, Toll-like receptor...

Abstract The epigenome responds to changes in the extracellular environment, yet how this information is transmitted epigenetic regulatory machinery unclear. Using a Saccharomyces cerevisiae yeast model, we demonstrate that target of rapamycin complex 1 (TORC1) signaling, which activated by nitrogen metabolism and amino acid availability, promotes site-specific acetylation histone H3 H4 N-terminal tails opposing activity sirtuin deacetylases Hst3 Hst4. TORC1 does so through suppression...

Abstract Background The target of rapamycin complex 1 (TORC1) is an evolutionarily conserved signal transduction pathway activated by environmental nutrients that regulates gene transcription to control cell growth and proliferation. How TORC1 modulates chromatin structure expression, however, largely unknown. Because a major transducer information, defining this process has critical implications for both understanding effects on epigenetic processes the role aberrant signaling in many...

The Ccr4-Not complex controls RNA polymerase II (Pol II) dependent gene expression and proteasome function. Not4 ubiquitin ligase is a subunit that has both RING domain conserved recognition motif C3H1 (referred to as the RRM-C domain) with unknown We demonstrate while individual or mutants fail replicate proteasomal defects found in deficient cells, mutation of exhibits loss function phenotype. Transcriptome analysis revealed affects specific subset Pol II-regulated genes, including those...

The Ccr4-Not complex contains the poorly understood Not4 ubiquitin ligase that functions in transcription, mRNA decay, translation, proteostasis, and endolysosomal nutrient signaling. To gain further insight into vivo of ligase, we performed quantitative proteomics Saccharomyces cerevisiae using yeast cells lacking Not4, or overexpressing wild-type an inactive mutant. Herein, provide evidence balanced activity maintains ribosomal protein (RP) homeostasis independent changes to RP known...

How cells respond and adapt to environmental changes, such as nutrient flux, remains poorly understood. Evolutionarily conserved signaling cascades can regulate chromatin contribute genome regulation cell adaptation, yet how they do so is only now beginning be elucidated. In this study, we provide evidence in yeast that the regulated target of rapamycin complex 1 (TORC1) pathway, histone H3N-terminus at lysine 37 (H3K37), function collaboratively restrict specific chromatin-binding high...

The Ccr4-Not complex functions as an effector of multiple signaling pathways that control gene transcription and mRNA turnover. Consequently, contributes to a diverse array processes, which includes significant role in cell metabolism. Yet mechanistic understanding how it metabolism is lacking. Herein, we provide evidence activates nutrient through the essential target rapamycin 1 (TORC1) pathway. disruption reduces global TORC1 signaling, also upregulates expression wall integrity (CWI)...

ABSTRACT The Ccr4-Not complex containing the Not4 ubiquitin ligase regulates gene transcription and mRNA decay, yet it also has poorly defined roles in translation, proteostasis, endolysosomal-dependent nutrient signaling. To define how mediated signaling these additional processes, we performed quantitative proteomics yeast Saccharomyces cerevisiae lacking ligase, cells overexpressing either wild-type or functionally inactive ligase. Herein, provide evidence that both increased decreased...