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Matthew D Galbraith, Heather Bender, Joaquín M Espinosa
The fact that many cancer types display transcriptional addiction driven by dysregulation of oncogenic enhancers and transcription factors has led to increased interest in a group of protein kinases, known as transcriptional cyclin dependent kinases (tCDKs), as potential therapeutic targets. Despite early reservations about targeting a process that is essential to healthy cell types, there is now evidence that targeting tCDKs could provide enough therapeutic window to be effective in the clinic. Here, we discuss recent developments in this field, with an emphasis on highly-selective inhibitors and the challenges to be addressed before these inhibitors could be used for therapeutic purposes...
November 9, 2018: Transcription
Alan C M Cheung, Luis Miguel Díaz-Santín
SAGA and NuA4 are coactivator complexes required for transcription on chromatin. Although they contain different enzymatic and biochemical activities, both contain the large Tra1 subunit. Recent electron microscopy studies have resolved the complete structure of Tra1 and its integration in SAGA/NuA4, providing important insight into Tra1 function.
October 30, 2018: Transcription
Andrew P Rice
Studies of RNA Polymerase II (Pol II) transcription of the HIV-1 genome are of clinical interest, as the insight gained may lead to strategies to selectively reactivate latent viruses in patients in whom viral replication is suppressed by antiviral drugs. Such a targeted reactivation may contribute to a functional cure of infection. This review discusses five Cyclin-dependent kinases - CDK7, CDK9, CDK11, CDK2, and CDK8 - involved in transcription and processing of HIV-1 RNA. CDK7 is required for Pol II promoter clearance of reactivated viruses; CDK7 also functions as an activating kinase for CDK9 when resting CD4+ T cells harboring latent HIV-1 are activated...
October 30, 2018: Transcription
Arno L Greenleaf
As the new millennium began, CDK12 and CDK13 were discovered as nucleotide sequences that encode protein kinases related to cell cycle CDKs. By the end of the first decade both proteins had been qualified as CTD kinases, and it was emerging that both are heterodimers containing a Cyclin K subunit. Since then, many studies on CDK12 have shown that, through phosphorylating the CTD of transcribing RNAPII, it plays critical roles in several stages of gene expression, notably RNA processing; it is also crucial for maintaining genome stability...
October 14, 2018: Transcription
Veronique Fischer, Kenny Schumacher, Laszlo Tora, Didier Devys
SAGA and TFIID are related transcription complexes, which were proposed to alternatively deliver TBP at different promoter classes. Recent genome-wide studies in yeast revealed that both complexes are required for the transcription of a vast majority of genes by RNA polymerase II raising new questions about the role of coactivators.
October 9, 2018: Transcription
Curtis W Bacon, Iván D'Orso
Cyclin-dependent kinase 9 (CDK9) is critical for RNA Polymerase II (Pol II) transcription initiation, elongation, and termination in several key biological processes including development, differentiation, and cell fate responses. A broad range of diseases are characterized by CDK9 malfunction, illustrating its importance in maintaining transcriptional homeostasis in basal- and signal-regulated conditions. Here we provide a historical recount of CDK9 discovery and the current models suggesting CDK9 is a central hub necessary for proper execution of different steps in the transcription cycle...
September 19, 2018: Transcription
Félix-Antoine Bérubé-Simard, Nicolas Pilon
CHARGE syndrome is characterized by co-occurrence of multiple malformations due to abnormal development of neural crest cells. Here, we review the phenotypic and molecular overlap between CHARGE syndrome and similar pathologies, and further discuss the observation that neural crest cells appear especially sensitive to malfunction of the chromatin-transcription-splicing molecular hub.
September 11, 2018: Transcription
Miquel Àngel Schikora-Tamarit, Lucas B Carey
Frameshifting errors are common and mRNA quality control pathways, such as nonsense-mediated decay (NMD), exist to degrade these aberrant transcripts. Recent work has shown the existence of a genetic link between NMD and codon-usage mediated mRNA decay. Here we present computational evidence that these pathways are synergic for removing frameshifts.
2018: Transcription
Himanshu S Raje, Molly E Lieux, Patrick J DiMario
The ribosomal RNA genes (rDNA) of Drosophila melanogaster reside within centromere-proximal nucleolar organizers on both the X and Y chromosomes. Each locus contains between 200-300 tandem repeat rDNA units that encode 18S, 5.8S, 2S, and 28S ribosomal RNAs (rRNAs) necessary for ribosome biogenesis. In arthropods like Drosophila, about 60% of the rDNA genes have R1 and/or R2 retrotransposons inserted at specific sites within their 28S regions; these units likely fail to produce functional 28S rRNA. We showed earlier that R2 expression increases upon nucleolar stress caused by the loss of the ribosome assembly factor, Nucleolar Phosphoprotein of 140 kDa (Nopp140)...
2018: Transcription
Joshua D Eaton, Steven West
Every transcription cycle ends in termination when RNA polymerase dissociates from the DNA. Although conceptually simple, the mechanism has proven somewhat elusive in eukaryotic systems. Gene-editing and high resolution polymerase mapping now offer clarification of important steps preceding transcriptional termination by RNA polymerase II in human cells.
2018: Transcription
Alasdair J E Gordon, Priya Sivaramakrishnan, Jennifer A Halliday, Christophe Herman
It was recently shown that removal of GreA, a transcription fidelity factor, enhances DNA break repair. This counterintuitive result, arising from unresolved backtracked RNA polymerase impeding DNA resection and thereby facilitating RecA-loading, leads to an interesting corollary: error-free full-length transcripts and broken chromosomes. Therefore, transcription fidelity may compromise genomic integrity.
2018: Transcription
Mark C Leake
High-speed single-molecule fluorescence microscopy in vivo shows that transcription factors in eukaryotes can act in oligomeric clusters mediated by molecular crowding and intrinsically disordered protein. This finding impacts on the longstanding puzzle of how transcription factors find their gene targets so efficiently in the complex, heterogeneous environment of the cell. Abbreviations CDF - cumulative distribution function; FRAP - fluorescence recovery after photobleaching; GFP - Green fluorescent protein; STORM - stochastic optical reconstruction microscopy; TF - Transcription factor; YFP - Yellow fluorescent protein...
2018: Transcription
Lan T M Dao, Salvatore Spicuglia
Promoters with enhancer activity have been described recently. In this point of view, we will discuss current findings highlighting the commonality of this type of regulatory elements, their genetic and epigenetic characteristics, their potential biological roles in the regulation of gene expression and the underlining molecular mechanisms. ABBREVIATIONS: TSS: transcription start site; IFN: interferon; STARR-seq: Self-Transcribing Active Regulatory Region sequencing; MPRA: Massively Parallel Reporter Assay; ChIP: chromatin immunoprecipitation; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; lncRNA: long non-coding RNA...
2018: Transcription
Daewoo Pak, Yunsoo Kim, Zachary F Burton
The genetic code sectored via tRNA charging errors, and the code progressed toward closure and universality because of evolution of aminoacyl-tRNA synthetase (aaRS) fidelity and translational fidelity mechanisms. Class I and class II aaRS folds are identified as homologs. From sequence alignments, a structurally conserved Zn-binding domain common to class I and class II aaRS was identified. A model for the class I and class II aaRS alternate folding pathways is posited. Five mechanisms toward code closure are highlighted: 1) aaRS proofreading to remove mischarged amino acids from tRNA; 2) accurate aaRS active site specification of amino acid substrates; 3) aaRS-tRNA anticodon recognition; 4) conformational coupling proofreading of the anticodon-codon interaction; and 5) deamination of tRNA wobble adenine to inosine...
2018: Transcription
Haruhiko Ehara, Shun-Ichi Sekine
Transcription by RNA polymerase II (Pol II) is accomplished with the aid of numerous accessory factors specific to each transcriptional stage. The structure of the Pol II elongation complex (EC) bound with Spt4/5, Elf1, and TFIIS unveiled the sophisticated basal EC architecture essential for transcription elongation and other transcription-related events.
2018: Transcription
Christina Julius, Amber Riaz-Bradley, Yulia Yuzenkova
Recently, it was found that bacterial and eukaryotic transcripts are capped with cellular cofactors installed by their respective RNA polymerases (RNAPs) during transcription initiation. We now show that mitochondrial RNAP efficiently caps transcripts with ADP - containing cofactors. However, a functional role of universal RNAP - catalysed capping is not yet clear.
2018: Transcription
Elise A Mahé, Thierry Madigou, Gilles Salbert
Zinc-finger and homeodomain transcription factors have been shown in vitro to bind to recognition motifs containing a methylated CpG. However, accessing these motifs in vivo might be seriously impeded by the inclusion of DNA in nucleosomes and by the condensed structure adopted by chromatin formed on methylated DNA. Here, we discuss how oxidation of 5-methylcytosine into 5-hydroxymethylcytosine could provide the initial destabilizing clue for such transcription factors to get access to nucleosomal DNA and read epigenetic information...
2018: Transcription
Daewoo Pak, Nan Du, Yunsoo Kim, Yanni Sun, Zachary F Burton
We advocate for a tRNA- rather than an mRNA-centric model for evolution of the genetic code. The mechanism for evolution of cloverleaf tRNA provides a root sequence for radiation of tRNAs and suggests a simplified understanding of code evolution. To analyze code sectoring, rooted tRNAomes were compared for several archaeal and one bacterial species. Rooting of tRNAome trees reveals conserved structures, indicating how the code was shaped during evolution and suggesting a model for evolution of a LUCA tRNAome tree...
2018: Transcription
Carlos Fernández-Tornero
In yeast, transcription of ribosomal DNA (rDNA) by RNA polymerase I (Pol I) is regulated by unique mechanisms acting at the level of the enzyme. Under stress situations such as starvation, Pol I hibernates through dimerization. When growth conditions are restored, dimer disassembly and Rrn3 binding drive enzyme activation and subsequent recruitment to rDNA.
2018: Transcription
Annemieke A Michels, Olivier Bensaude
Hexim1 acts as a tumor suppressor and is involved in the regulation of innate immunity. It was initially described as a non-coding RNA-dependent regulator of transcription. Here, we detail how 7SK RNA binds to Hexim1 and turns it into an inhibitor of the positive transcription elongation factor (P-TEFb). In addition to its action on P-TEFb, it plays a role in a variety of different mechanisms: it controls the stability of transcription factor components and assists binding of transcription factors to their targets...
2018: Transcription
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