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https://www.readbyqxmd.com/read/27863397/targeting-gli-by-gant61-involves-mechanisms-dependent-on-inhibition-of-both-transcription-and-dna-licensing
#1
Ruowen Zhang, Jiahui Wu, Sylvain Ferrandon, Katie J Glowacki, Janet A Houghton
The GLI genes are transcription factors and in cancers are oncogenes, aberrantly and constitutively activated. GANT61, a specific GLI inhibitor, has induced extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops (RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27833949/the-emerging-picture-of-cdk9-p-tefb-more-than-20-years-of-advances-since-pitalre
#2
REVIEW
Nikolas Ferreira Dos Santos Paparidis, Maxwell Castro Durvale, Fernanda Canduri
CDK9 is a prominent member of the transcriptional CDKs subfamily, a group of kinases whose function is to control the primary steps of mRNA synthesis and processing by eukaryotic RNA polymerase II. As a cyclin-dependent kinase, CDK9 activation in vivo depends upon its association with T-type cyclins to assemble the positive transcription elongation factor (P-TEFb). Although CDK9/P-TEFb phosphorylates the C-terminal domain of RNAP II in the same positions targeted by CDK7 (TFIIH) and CDK8 (Mediator), the former does not participate in the transcription initiation, but rather plays a unique role by driving the polymerase to productive elongation...
November 11, 2016: Molecular BioSystems
https://www.readbyqxmd.com/read/27803842/what-do-we-learn-from-the-murine-jacob-nsmf-gene-knockout-for-human-disease
#3
Christina Spilker, Katarzyna M Grochowska, Michael R Kreutz
Mutations in the NSMF gene have been related to Kallmann syndrome. Conflicting results have been reported on the subcellular localization of Jacob/NELF, the protein encoded by the NSMF gene. Some reports indicate an extracellular localization and a function as a guidance molecule for migration of GnRH-positive neurons from the olfactory placode to the hypothalamus. Other studies have shown protein transport of Jacob from synapse-to-nucleus and indicate a role of the protein in neuronal activity-dependent gene expression...
2016: Rare Diseases
https://www.readbyqxmd.com/read/27716820/gdown1-associates-efficiently-with-rna-polymerase-ii-after-promoter-clearance-and-displaces-tfiif-during-transcript-elongation
#4
Elizabeth DeLaney, Donal S Luse
Pausing during the earliest stage of transcript elongation by RNA polymerase II (Pol II) is a nearly universal control point in metazoan gene expression. The substoichiometric Pol II subunit Gdown1 facilitates promoter proximal pausing in vitro in extract-based transcription reactions, out-competes the initiation/elongation factor TFIIF for binding to free Pol II and co-localizes with paused Pol II in vivo. However, we have shown that Gdown1 cannot functionally associate with the Pol II preinitiation complex (PIC), which contains TFIIF...
2016: PloS One
https://www.readbyqxmd.com/read/27468311/gaga-factor-a-positive-regulator-of-global-gene-expression-modulates-transcriptional-pausing-and-organization-of-upstream-nucleosomes
#5
Shih-Ying Tsai, Yuh-Long Chang, Krishna B S Swamy, Ruei-Lin Chiang, Der-Hwa Huang
BACKGROUND: Genome-wide studies in higher eukaryotes have revealed the presence of paused RNA polymerase II (RNA-Pol) at about 30-50 bp downstream of the transcription start site of genes involved in developmental control, cell proliferation and intercellular signaling. Promoter-proximal pausing is believed to represent a critical step in transcriptional regulation. GAGA sequence motifs have frequently been found in the upstream region of paused genes in Drosophila, implicating a prevalent binding factor, GAF, in transcriptional pausing...
2016: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/27353326/multiple-p-tefbs-cooperatively-regulate-the-release-of-promoter-proximally-paused-rna-polymerase-ii
#6
Xiaodong Lu, Xinxing Zhu, You Li, Min Liu, Bin Yu, Yu Wang, Muhua Rao, Haiyang Yang, Kai Zhou, Yao Wang, Yanheng Chen, Meihua Chen, Songkuan Zhuang, Lin-Feng Chen, Runzhong Liu, Ruichuan Chen
The association of DSIF and NELF with initiated RNA Polymerase II (Pol II) is the general mechanism for inducing promoter-proximal pausing of Pol II. However, it remains largely unclear how the paused Pol II is released in response to stimulation. Here, we show that the release of the paused Pol II is cooperatively regulated by multiple P-TEFbs which are recruited by bromodomain-containing protein Brd4 and super elongation complex (SEC) via different recruitment mechanisms. Upon stimulation, Brd4 recruits P-TEFb to Spt5/DSIF via a recruitment pathway consisting of Med1, Med23 and Tat-SF1, whereas SEC recruits P-TEFb to NELF-A and NELF-E via Paf1c and Med26, respectively...
August 19, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27282391/architecture-and-rna-binding-of-the-human-negative-elongation-factor
#7
Seychelle M Vos, David Pöllmann, Livia Caizzi, Katharina B Hofmann, Pascaline Rombaut, Tomasz Zimniak, Franz Herzog, Patrick Cramer
Transcription regulation in metazoans often involves promoter-proximal pausing of RNA polymerase (Pol) II, which requires the 4-subunit negative elongation factor (NELF). Here we discern the functional architecture of human NELF through X-ray crystallography, protein crosslinking, biochemical assays, and RNA crosslinking in cells. We identify a NELF core subcomplex formed by conserved regions in subunits NELF-A and NELF-C, and resolve its crystal structure. The NELF-AC subcomplex binds single-stranded nucleic acids in vitro, and NELF-C associates with RNA in vivo...
2016: ELife
https://www.readbyqxmd.com/read/27256882/chemical-genetic-discovery-of-parp-targets-reveals-a-role-for-parp-1-in-transcription-elongation
#8
Bryan A Gibson, Yajie Zhang, Hong Jiang, Kristine M Hussey, Jonathan H Shrimp, Hening Lin, Frank Schwede, Yonghao Yu, W Lee Kraus
Poly[adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are a family of enzymes that modulate diverse biological processes through covalent transfer of ADP-ribose from the oxidized form of nicotinamide adenine dinucleotide (NAD(+)) onto substrate proteins. Here we report a robust NAD(+) analog-sensitive approach for PARPs, which allows PARP-specific ADP-ribosylation of substrates that is suitable for subsequent copper-catalyzed azide-alkyne cycloaddition reactions. Using this approach, we mapped hundreds of sites of ADP-ribosylation for PARPs 1, 2, and 3 across the proteome, as well as thousands of PARP-1-mediated ADP-ribosylation sites across the genome...
July 1, 2016: Science
https://www.readbyqxmd.com/read/27177472/mir-1236-regulates-hypoxia-induced-epithelial-mesenchymal-transition-and-cell-migration-invasion-through-repressing-senp1-and-hdac3
#9
Sung-Yuan Chen, Shu-Chun Teng, Tzu-Hao Cheng, Kou-Juey Wu
Intratumoral hypoxia induces epithelial-mesenchymal transition and promotes cancer metastasis. MicroRNAs (miRNAs) are endogenous, single-strand RNA molecules that regulate gene expression. MiRNAs control cell growth, proliferation, differentiation and cell death and may function as oncogenes or tumor suppressors. HDAC3 and SENP1 are two molecules involved in hypoxia-induced EMT and HIF-1α stability, respectively. In this report, we show that miR-1236 plays a critical role in hypoxia-induced EMT and metastasis...
August 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/26941120/genetic-suppression-reveals-dna-repair-independent-antagonism-between-brca1-and-cobra1-in-mammary-gland-development
#10
Sreejith J Nair, Xiaowen Zhang, Huai-Chin Chiang, Md Jamiul Jahid, Yao Wang, Paula Garza, Craig April, Neeraj Salathia, Tapahsama Banerjee, Fahad S Alenazi, Jianhua Ruan, Jian-Bing Fan, Jeffrey D Parvin, Victor X Jin, Yanfen Hu, Rong Li
The breast cancer susceptibility gene BRCA1 is well known for its function in double-strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. COBRA1 (also known as NELF-B) is a BRCA1-binding protein that regulates RNA polymerase II (RNAPII) pausing and transcription elongation. Here we interrogate functional interaction between BRCA1 and COBRA1 during mouse mammary gland development. Tissue-specific deletion of Cobra1 reduces mammary epithelial compartments and blocks ductal morphogenesis, alveologenesis and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development...
March 4, 2016: Nature Communications
https://www.readbyqxmd.com/read/26813131/-association-of-the-extra-gonadal-manifestations-with-different-pathogenic-gene-mutations-in-male-patients-with-congenital-hypogonadotropic-hypogonadism
#11
Jiangfeng Mao, Rongrong Chen, Xueyan Wu, Zhaoxiang Liu, Junjie Zheng, Xi Wang, Min Nie, Jing Duan, Hongbing Zhang
OBJECTIVE: To explore the relationships between pathogenic gene mutations and extra-gonadal manifestations in male patients with congenital hypogonadotropic hypogonadism (CHH). METHODS: A total of 15 genes were screened in 259 CHH patients by massively parallel DNA sequencing. The identified pathogenic mutations were confirmed by Sanger polymerase chain reaction (PCR). The extra-gonadal features in all patients were recorded. RESULTS: Gene mutations were detected in 83 (32...
November 10, 2015: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/26549458/histone-deacetylases-positively-regulate-transcription-through-the-elongation-machinery
#12
Celeste B Greer, Yoshiaki Tanaka, Yoon Jung Kim, Peng Xie, Michael Q Zhang, In-Hyun Park, Tae Hoon Kim
Transcription elongation regulates the expression of many genes, including oncogenes. Histone deacetylase (HDAC) inhibitors (HDACIs) block elongation, suggesting that HDACs are involved in gene activation. To understand this, we analyzed nascent transcription and elongation factor binding genome-wide after perturbation of elongation with small molecule inhibitors. We found that HDACI-mediated repression requires heat shock protein 90 (HSP90) activity. HDACIs promote the association of RNA polymerase II (RNAP2) and negative elongation factor (NELF), a complex stabilized by HSP90, at the same genomic sites...
November 17, 2015: Cell Reports
https://www.readbyqxmd.com/read/26504077/kinetically-defined-mechanisms-and-positions-of-action-of-two-new-modulators-of-glucocorticoid-receptor-regulated-gene-induction
#13
Madhumita A Pradhan, John A Blackford, Ballachanda N Devaiah, Petria S Thompson, Carson C Chow, Dinah S Singer, S Stoney Simons
Most of the steps in, and many of the factors contributing to, glucocorticoid receptor (GR)-regulated gene induction are currently unknown. A competition assay, based on a validated chemical kinetic model of steroid hormone action, is now used to identify two new factors (BRD4 and negative elongation factor (NELF)-E) and to define their sites and mechanisms of action. BRD4 is a kinase involved in numerous initial steps of gene induction. Consistent with its complicated biochemistry, BRD4 is shown to alter both the maximal activity (Amax) and the steroid concentration required for half-maximal induction (EC50) of GR-mediated gene expression by acting at a minimum of three different kinetically defined steps...
January 1, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26379089/rnap-ii-processivity-is-a-limiting-step-for-hiv-1-transcription-independent-of-orientation-to-and-activity-of-endogenous-neighboring-promoters
#14
Katarzyna Kaczmarek Michaels, Frank Wolschendorf, Gillian M Schiralli Lester, Malini Natarajan, Olaf Kutsch, Andrew J Henderson
Since HIV-1 has a propensity to integrate into actively expressed genes, transcriptional interference from neighboring host promoters has been proposed to contribute to the establishment and maintenance HIV-1 latency. To gain insights into how endogenous promoters influence HIV-1 transcription we utilized a set of inducible T cell lines and characterized whether there were correlations between expression of endogenous genes, provirus and long terminal repeat architecture. We show that neighboring promoters are active but have minimal impact on HIV-1 transcription, in particular, expression of the endogenous gene did not prevent expression of HIV-1 following induction of latent provirus...
December 2015: Virology
https://www.readbyqxmd.com/read/26340924/nf-%C3%AE%C2%BAb-repressing-factor-phosphorylation-regulates-transcription-elongation-via-its-interactions-with-5-%C3%A2-3-exoribonuclease-2-and-negative-elongation-factor
#15
Sascha Rother, Myriam Bartels, Aike Torben Schweda, Klaus Resch, Norbert Pallua, Mahtab Nourbakhsh
NF-κB-repressing factor (NKRF) inhibits transcription elongation by binding to specific sequences in target promoters. Stimuli such as IL-1 have been shown to overcome this inhibitory action and enable the resumption of transcription elongation machinery by an unknown mechanism. Using mass spectrometry and in vitro phosphorylation analyses, we demonstrate that NKRF is phosphorylated within 3 different domains in unstimulated HeLa cells. Phosphoamino acid mapping and mutation analysis of NKRF further suggest that only Ser phosphorylation within aa 421-429 is regulated by IL-1 stimulation...
January 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/26257281/thz1-reveals-roles-for-cdk7-in-co-transcriptional-capping-and-pausing
#16
Kyle A Nilson, Jiannan Guo, Michael E Turek, John E Brogie, Elizabeth Delaney, Donal S Luse, David H Price
The Cdk7 subunit of TFIIH phosphorylates RNA polymerase II (Pol II) during initiation, and, while recent studies show that inhibition of human Cdk7 negatively influences transcription, the mechanisms involved are unclear. Using in vitro transcription with nuclear extract, we demonstrate that THZ1, a covalent Cdk7 inhibitor, causes defects in Pol II phosphorylation, co-transcriptional capping, promoter proximal pausing, and productive elongation. THZ1 does not affect initiation but blocks essentially all Pol II large subunit C-terminal domain (CTD) phosphorylation...
August 20, 2015: Molecular Cell
https://www.readbyqxmd.com/read/26199944/novel-fgfr1-and-kiss1r-mutations-in-chinese-kallmann-syndrome-males-with-cleft-lip-palate
#17
Hao Xu, Yonghua Niu, Tao Wang, Simin Liu, Hua Xu, Shaogang Wang, Jihong Liu, Zhangqun Ye
Kallmann syndrome (KS) is characterized by isolated hypogonadotropic hypogonadism (IHH) with anosmia and is sometimes associated with cleft lip/palate (CLP). In order to describe the clinical features, genetic etiology, and treatment outcome of KS males with CLP, we performed genetic screening for 15 known causal IHH genes (KAL1, FGFR1, NELF, FGF8, CHD7, WDR11, SEMA3A, KISS1R, KISS1, PROKR2, PROK2, TAC3, TACR3, GNRH1, and GNRHR) in four KS with CLP patients and six IHH patients without CLP. Two novel heterozygous missense mutations in FGFR1, (NM_001174066): c...
2015: BioMed Research International
https://www.readbyqxmd.com/read/26182240/quantitative-assessment-of-rna-protein-interactions-with-high-throughput-sequencing-rna-affinity-profiling
#18
Abdullah Ozer, Jacob M Tome, Robin C Friedman, Dan Gheba, Gary P Schroth, John T Lis
Because RNA-protein interactions have a central role in a wide array of biological processes, methods that enable a quantitative assessment of these interactions in a high-throughput manner are in great demand. Recently, we developed the high-throughput sequencing-RNA affinity profiling (HiTS-RAP) assay that couples sequencing on an Illumina GAIIx genome analyzer with the quantitative assessment of protein-RNA interactions. This assay is able to analyze interactions between one or possibly several proteins with millions of different RNAs in a single experiment...
August 2015: Nature Protocols
https://www.readbyqxmd.com/read/26010750/translational-initiation-at-a-non-aug-start-codon-for-human-and-mouse-negative-elongation-factor-b
#19
Haihui Pan, Xiayan Zhao, Xiaowen Zhang, Mohamed Abouelsoud, Jianlong Sun, Craig April, Asma Amleh, Jian-Bing Fan, Yanfen Hu, Rong Li
Negative elongation factor (NELF), a four-subunit protein complex in metazoan, plays an important role in regulating promoter-proximal pausing of RNA polymerase II (RNAPII). Genetic studies demonstrate that the B subunit of mouse NELF (NELF-B) is critical for embryonic development and homeostasis in adult tissue. We report here that both human and mouse NELF-B proteins are translated from a non-AUG codon upstream of the annotated AUG. This non-AUG codon sequence is conserved in mammalian NELF-B but not NELF-B orthologs of lower metazoan...
2015: PloS One
https://www.readbyqxmd.com/read/25936800/smads-and-yap-compete-to-control-elongation-of-%C3%AE-catenin-lef-1-recruited-rnapii-during-hesc-differentiation
#20
Conchi Estarás, Chris Benner, Katherine A Jones
The Wnt3a/β-catenin and Activin/SMAD2,3 signaling pathways synergize to induce endodermal differentiation of human embryonic stem cells; however, the underlying mechanism is not well understood. Using ChIP-seq and GRO-seq analyses, we show here that Wnt3a-induced β-catenin:LEF-1 enhancers recruit cohesin to direct enhancer-promoter looping and activate mesendodermal (ME) lineage genes. Moreover, we find that LEF-1 and other hESC enhancers recruit RNAPII complexes (eRNAPII) that are highly phosphorylated at Ser5, but not Ser7...
June 4, 2015: Molecular Cell
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