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https://www.readbyqxmd.com/read/28623239/-ccug-n-rna-toxicity-in-a-drosophila-model-for-myotonic-dystrophy-type-2-dm2-activates-apoptosis
#1
Vildan Betul Yenigun, Mario Sirito, Alla Amcheslavky, Tomek Czernuszewicz, Jordi Colonques-Bellmunt, Irma García-Alcover, Marzena Wojciechowska, Clare Bolduc, Zhihong Chen, Arturo López Castel, Ralf Krahe, Andreas Bergmann
The myotonic dystrophies are prototypic toxic RNA gain-of-function diseases. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by different unstable, noncoding microsatellite repeat expansions -- (CTG)DM1 in DMPK and (CCTG)DM2 in CNBP Although transcription of mutant repeats into (CUG)DM1 or (CCUG)DM2 appears to be necessary and sufficient to cause disease, their pathomechanisms remain incompletely understood. To study the mechanisms of (CCUG)DM2 toxicity and develop a convenient model for drug screening, we generated a transgenic DM2 model in the fruit fly Drosophila melanogaster with (CCUG)n repeats of variable length (n=16 and 106)...
June 16, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28609657/ack1-tnk2-regulates-histone-h4-tyr88-phosphorylation-and-ar-gene-expression-in-castration-resistant-prostate-cancer
#2
Kiran Mahajan, Pavani Malla, Harshani R Lawrence, Zhihua Chen, Chandan Kumar-Sinha, Rohit Malik, Sudhanshu Shukla, Jongphil Kim, Domenico Coppola, Nicholas J Lawrence, Nupam P Mahajan
The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription...
June 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28604729/dnmt-and-hdac-inhibitors-induce-cryptic-transcription-start-sites-encoded-in-long-terminal-repeats
#3
David Brocks, Christopher R Schmidt, Michael Daskalakis, Hyo Sik Jang, Nakul M Shah, Daofeng Li, Jing Li, Bo Zhang, Yiran Hou, Sara Laudato, Daniel B Lipka, Johanna Schott, Holger Bierhoff, Yassen Assenov, Monika Helf, Alzbeta Ressnerova, Md Saiful Islam, Anders M Lindroth, Simon Haas, Marieke Essers, Charles D Imbusch, Benedikt Brors, Ina Oehme, Olaf Witt, Michael Lübbert, Jan-Philipp Mallm, Karsten Rippe, Rainer Will, Dieter Weichenhan, Georg Stoecklin, Clarissa Gerhäuser, Christopher C Oakes, Ting Wang, Christoph Plass
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions...
June 12, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28601608/activation-of-unfolded-protein-response-pathway-is-important-for-valproic-acid-mediated-increase-in-immunoglobulin-g-productivity-in-recombinant-chinese-hamster-ovary-cells
#4
Kamal Prashad Segar, Vikas Chandrawanshi, Sarika Mehra
Process engineering to improve product quality and titers is gaining importance at late-stage cell culture process development. Valproic acid, a US Food and Drug Administration-approved histone deacetylase (HDAC) inhibitor, has been shown to improve cell culture performance with higher productivities and minimal effect on the product quality. However, the wider physiological impact of valproic acid on recombinant cells has not been investigated till date. In this study, we investigate the role of unfolded protein response pathway when immunoglobulin G (IgG)-secreting Chinese hamster ovary (CHO) cells are treated with valproic acid, resulting in a 3-fold increase in product titers and productivity...
June 7, 2017: Journal of Bioscience and Bioengineering
https://www.readbyqxmd.com/read/28600226/screening-for-small-molecule-inhibitors-of-hiv-1-gag-expression
#5
Ahalya Balachandran, Alan Cochrane
The control of RNA processing plays an important role in the nature and quantity of protein generated from mammalian genes. Consequently, efforts to manipulate RNA processing have the capacity to significantly impact gene function. Although multiple strategies have been developed to alter splice site selection using oligonucleotide occlusion of splice sites or splicing regulatory elements, systemic delivery of such agents remains problematic. Outlined in this chapter is a protocol to screen for small molecule inhibitors of HIV-1 Gag expression that have been subsequently determined to modulate viral RNA processing...
June 17, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28599273/targeting-bcr-abl-stem-progenitor-cells-and-bcr-abl-t315i-mutant-cells-by-effective-inhibition-of-the-bcr-abl-tyr177-grb2-complex
#6
Min Chen, Ali G Turhan, Hongxia Ding, Qingcong Lin, Kun Meng, Xiaoyan Jiang
Treatment of BCR-ABL+ human leukemia has been significantly improved by ABL tyrosine kinase inhibitors (TKIs), but they are not curative for most patients and relapses are frequently associated with BCR-ABL mutations, warranting new targets for improved treatments. We have now demonstrated that protein expression of human estrogen receptor alpha 36 (ERα36), an alternative splicing variant of human estrogen receptor alpha 66 (ERα66), is highly increased in TKI-insensitive CD34+ chronic myeloid leukemia (CML) cells and BCR-ABL-T315I mutant cells, and is abnormally localized in plasma membrane and cytoplasm...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28592699/lower-affinity-of-isradipine-for-l-type-ca-2-channels-during-substantia-nigra-dopamine-neuron-like-activity-implications-for-neuroprotection-in-parkinson-s-disease
#7
Nadine J Ortner, Gabriella Bock, Antonios Dougalis, Maria Kharitonova, Johanna Duda, Simon Hess, Petronel Tuluc, Thomas Pomberger, Nadia Stefanova, Florian Pitterl, Thomas Ciossek, Herbert Oberacher, Henning J Draheim, Peter Kloppenburg, Birgit Liss, Jörg Striessnig
Ca(2+)-influx through L-type Ca(2+)-channels (LTCCs) is associated with activity-related stressful oscillations of Ca(2+)-levels within dopaminergic (DA) neurons in the substantia nigra (SN), which may contribute to their selective degeneration in Parkinson's disease (PD). LTCC blockers were neuroprotective in mouse neurotoxin models of PD and isradipine is currently undergoing testing in a phase-III clinical trial in early PD. We report no evidence for neuroprotection by in vivo pretreatment with therapeutically relevant isradipine plasma levels, or Cav1...
June 7, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28592461/rbm24-promotes-u1-snrnp-recognition-of-the-mutated-5-splice-site-in-the-ikbkap-gene-of-familial-dysautonomia
#8
Kenji Ohe, Mayumi Yoshida, Akiko Nakano-Kobayashi, Motoyasu Hosokawa, Yukiya Sako, Maki Sakuma, Yukiko Okuno, Tomomi Usui, Kensuke Ninomiya, Takayuki Nojima, Naoyuki Kataoka, Masatoshi Hagiwara
The 5' splice site mutation (IVS20+6T>C) of the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene in familial dysautonomia (FD) is at the sixth intronic nucleotide of the 5' splice site. It is known to weaken U1 snRNP recognition and result in aberrantly spliced mRNA product in neuronal tissue, but normally spliced mRNA in other tissues. Aberrantly spliced IKBKAP mRNA abrogates IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1) expression and results in a defect of neuronal cell development in FD...
June 7, 2017: RNA
https://www.readbyqxmd.com/read/28580641/melatonin-reduces-endoplasmic-reticulum-stress-and-corneal-dystrophy-associated-tgfbip-through-activation-of-endoplasmic-reticulum-associated-protein-degradation
#9
Seung-Il Choi, Eunhee Lee, Begum Akuzum, Jang Bin Jeong, Yong-Sun Maeng, Tae-Im Kim, Eung Kweon Kim
Endoplasmic reticulum (ER) stress is emerging as a factor for the pathogenesis of granular corneal dystrophy type 2 (GCD2). This study was designed to investigate the molecular mechanisms underlying the protective effects of melatonin on ER stress in GCD2. Our results showed that GCD2 corneal fibroblasts were more susceptible to ER stress-induced death than were wild-type cells. Melatonin significantly inhibited GCD2 corneal cell death, caspase-3 activation, and poly (ADP-ribose) polymerase 1 cleavage caused by the ER stress inducer, tunicamycin...
June 5, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28578669/vegf-isoforms-have-differential-effects-on-permeability-of-human-pulmonary-microvascular-endothelial-cells
#10
Khadija Ourradi, Thomas Blythe, Caroline Jarrett, Shaney L Barratt, Gavin I Welsh, Ann B Millar
BACKGROUND: Alternative splicing of Vascular endothelial growth factor-A mRNA transcripts (commonly referred as VEGF) leads to the generation of functionally differing isoforms, the relative amounts of which have potentially significant physiological outcomes in conditions such as acute respiratory distress syndrome (ARDS). The effect of such isoforms on pulmonary vascular permeability is unknown. We hypothesised that VEGF165a and VEGF165b isoforms would have differing effects on pulmonary vascular permeability caused by differential activation of intercellular signal transduction pathways...
June 2, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28571741/circular-rna-hsa_circ_0010729-regulates-vascular-endothelial-cell-proliferation-and-apoptosis-by-targeting-the-mir-186-hif-1%C3%AE-axis
#11
Rui-Ying Dang, Feng-Li Liu, Yan Li
Circular RNAs (circRNAs) are a group of non-protein-coding RNAs generated from back splicing. Emerging evidence has demonstrated its vital regulation on angiogenesis. However, the underlying mechanism responsible for circRNAs effects on vascular endothelial cells is still unclear. In the present study, we screened the expression profiles and investigated the physiological role of circRNAs in hypoxia-induced human umbilical vein endothelial cells (HUVECs). Using circRNA microarray analysis, we identified 36 circRNAs that were significantly dysregulated including 14 down-regulated circRNAs and 22 up-regulated with 2-fold change (P < 0...
May 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28559488/viral-dna-replication-orientation-and-hnrnps-regulate-transcription-of-the-human-papillomavirus-18-late-promoter
#12
Xiaohong Wang, Haibin Liu, Hui Ge, Masahiko Ajiro, Nishi R Sharma, Craig Meyers, Pavel Morozov, Thomas Tuschl, Amar Klar, Donald Court, Zhi-Ming Zheng
The life cycle of human papillomaviruses (HPVs) is tightly linked to keratinocyte differentiation. Although expression of viral early genes is initiated immediately upon virus infection of undifferentiated basal cells, viral DNA amplification and late gene expression occur only in the mid to upper strata of the keratinocytes undergoing terminal differentiation. In this report, we show that the relative activity of HPV18 TATA-less late promoter P811 depends on its orientation relative to that of the origin (Ori) of viral DNA replication and is sensitive to the eukaryotic DNA polymerase inhibitor aphidicolin...
May 30, 2017: MBio
https://www.readbyqxmd.com/read/28559265/hbv-capsid-assembly-modulators-but-not-nucleoside-analogs-inhibit-the-production-of-extracellular-pregenomic-rna-and-spliced-rna-variants
#13
Angela M Lam, Suping Ren, Christine Espiritu, Mollie Kelly, Vincent Lau, Lingjie Zheng, George D Hartman, Osvaldo A Flores, Klaus Klumpp
The Hepatitis B virus (HBV) core protein serves multiple essential functions in the viral life cycle and is being developed as a target for antiviral agents. Capsid assembly modulators (CAMs) are compounds that target core and misdirect capsid assembly, resulting in the suppression of HBV replication and virion production. Besides HBV DNA, circulating HBV RNA has been detected in patient serum and can be associated with treatment response. Here we studied the effect of HBV CAMs on the production of extracellular HBV RNA using infected HepaRG cells and primary human hepatocytes...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28558059/multivalent-peptidic-linker-enables-identification-of-preferred-sites-of-conjugation-for-a-potent-thialanstatin-antibody-drug-conjugate
#14
Sujiet Puthenveetil, Haiyin He, Frank Loganzo, Sylvia Musto, Jesse Teske, Michael Green, Xingzhi Tan, Christine Hosselet, Judy Lucas, L Nathan Tumey, Puja Sapra, Chakrapani Subramanyam, Christopher J O'Donnell, Edmund I Graziani
Antibody drug conjugates (ADCs) are no longer an unknown entity in the field of cancer therapy with the success of marketed ADCs like ADCETRIS and KADCYLA and numerous others advancing through clinical trials. The pursuit of novel cytotoxic payloads beyond the mictotubule inhibitors and DNA damaging agents has led us to the recent discovery of an mRNA splicing inhibitor, thailanstatin, as a potent ADC payload. In our previous work, we observed that the potency of this payload was uniquely tied to the method of conjugation, with lysine conjugates showing much superior potency as compared to cysteine conjugates...
2017: PloS One
https://www.readbyqxmd.com/read/28555643/development-of-an-orally-available-inhibitor-of-clk1-for-skipping-a-mutated-dystrophin-exon-in-duchenne-muscular-dystrophy
#15
Yukiya Sako, Kensuke Ninomiya, Yukiko Okuno, Masayasu Toyomoto, Atsushi Nishida, Yuka Koike, Kenji Ohe, Isao Kii, Suguru Yoshida, Naohiro Hashimoto, Takamitsu Hosoya, Masafumi Matsuo, Masatoshi Hagiwara
Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD to a milder phenotype by modulating the splicing of the dystrophin gene and restoring its expression. In our previous study, we reported TG003, an inhibitor of CDC2-like kinase 1 (CLK1), as a splice-modifying compound for exon-skipping therapy; however, its metabolically unstable feature hinders clinical application. Here, we show an orally available inhibitor of CLK1, named TG693, which promoted the skipping of the endogenous mutated exon 31 in DMD patient-derived cells and increased the production of the functional exon 31-skipped dystrophin protein...
May 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28554943/spink2-deficiency-causes-infertility-by-inducing-sperm-defects-in-heterozygotes-and-azoospermia-in%C3%A2-homozygotes
#16
Zine-Eddine Kherraf, Marie Christou-Kent, Thomas Karaouzene, Amir Amiri-Yekta, Guillaume Martinez, Alexandra S Vargas, Emeline Lambert, Christelle Borel, Béatrice Dorphin, Isabelle Aknin-Seifer, Michael J Mitchell, Catherine Metzler-Guillemain, Jessica Escoffier, Serge Nef, Mariane Grepillat, Nicolas Thierry-Mieg, Véronique Satre, Marc Bailly, Florence Boitrelle, Karin Pernet-Gallay, Sylviane Hennebicq, Julien Fauré, Serge P Bottari, Charles Coutton, Pierre F Ray, Christophe Arnoult
Azoospermia, characterized by the absence of spermatozoa in the ejaculate, is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings, we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility...
May 29, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28547672/myeloid-neoplasms-with-germline-ddx41-mutation
#17
REVIEW
Jesse J C Cheah, Christopher N Hahn, Devendra K Hiwase, Hamish S Scott, Anna L Brown
Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context...
May 25, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28542039/role-of-the-uridine-cytidine-kinase-2-mutation-in-cellular-sensitiveness-toward-3-ethynylcytidine-treatment-of-human-cancer-cells
#18
Akira Sato, Takeshi Takano, Akiko Hiramoto, Tomoharu Naito, Akira Matsuda, Masakazu Fukushima, Yusuke Wataya, Hye-Sook Kim
A nucleosidic medicine, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine [3'-ethynylcytidine (ECyd)], is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors in vitro and in vivo. ECyd is phosphorylated to 3'-ethyntlcytidine 5'-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3'-ethyntlcytidine 5'-diphosphate, 3'-ethyntlcytidine 5'-triphosphate). 3'-Ethyntlcytidine 5'-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively, causing cancer cell death...
May 24, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28535287/a-flow-cytometry-based-screen-identifies-mbnl1-modulators-that-rescue-splicing-defects-in-myotonic-dystrophy-type-i
#19
Fan Zhang, Nicole E Bodycombe, Keith M Haskell, Yumei L Sun, Eric T Wang, Carl A Morris, Lyn H Jones, Lauren D Wood, Mathew T Pletcher
Myotonic Dystrophy Type 1 (DM1) is a rare genetic disease caused by expansion of CTG trinucleotide repeats ((CTG)exp) in the 3' untranslated region of the DMPK gene. The repeat transcripts sequester the RNA binding protein Muscleblind-like protein 1 (MBNL1) and hamper its normal function in pre-mRNA splicing. Overexpressing exogenous MBNL1 in the DM1 mouse model has been shown to rescue the splicing defects and reverse myotonia. Although a viable therapeutic strategy, pharmacological modulators of MBNL1 expression have not been identified...
May 23, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28533324/crispr-cas9-genetic-modification-of-cyp3a5-3-in-huh-7-human-hepatocyte-cell-line-leads-to-cell-lines-with-increased-midazolam-and-tacrolimus-metabolism
#20
Casey R Dorr, Rory P Remmel, Amutha Muthusamy, James Fisher, Branden Moriarity, Kazuto Yasuda, Baolin Wu, Weihua Guan, Erin G Schuetz, William S Oetting, Pamala A Jacobson, Ajay K Israni
CRISPR/Cas9 engineering of the CYP3A5 *3 locus (rs776746) in human liver cell line HuH-7 (CYP3A5 *3/*3) led to three CYP3A5 *1 cell lines by deletion of the exon 3B splice junction or point mutation. Cell lines CYP3A5 *1/*3 sd (single deletion), CYP3A5 *1/*1 dd (double deletion) or CYP3A5 *1/*3 pm (point mutation) expressed the CYP3A5 *1 mRNA, had elevated CYP3A5 mRNA (p<0.0005 for all engineered cell lines) and protein expression compared with HuH-7. In metabolism assays, HuH-7 had less tacrolimus (Tac) (all p-values < 0...
May 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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