Genome-Wide Analyses of XRN1-Sensitive Targets in Osteosarcoma Cells Identifies Disease-Relevant 2 Transcripts Containing G-Rich Motifs
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NUDT15 Hydrolyzes 6-Thio-Deoxygtp to Mediate the Anticancer Efficacy of 6-Thioguanine Nicholas C.K
Published OnlineFirst August 16, 2016; DOI: 10.1158/0008-5472.CAN-16-0584 Cancer Therapeutics, Targets, and Chemical Biology Research NUDT15 Hydrolyzes 6-Thio-DeoxyGTP to Mediate the Anticancer Efficacy of 6-Thioguanine Nicholas C.K. Valerie1, Anna Hagenkort1, Brent D.G. Page1, Geoffrey Masuyer2, Daniel Rehling2, Megan Carter2, Luka Bevc1, Patrick Herr1, Evert Homan1, Nina G. Sheppard1, Pa l Stenmark2, Ann-Sofie Jemth1, and Thomas Helleday1 Abstract Thiopurines are a standard treatment for childhood leuke- for NUDT15, a finding supported by a crystallographic deter- mia, but like all chemotherapeutics, their use is limited by mination of NUDT15 in complex with 6-thio-GMP. We found inherent or acquired resistance in patients. Recently, the nucle- that NUDT15 R139C mutation did not affect enzymatic activity oside diphosphate hydrolase NUDT15 has received attention on but instead negatively influenced protein stability, likely due to the basis of its ability to hydrolyze the thiopurine effector a loss of supportive intramolecular bonds that caused rapid metabolites 6-thio-deoxyGTP (6-thio-dGTP) and 6-thio-GTP, proteasomal degradation in cells. Mechanistic investigations in thereby limiting the efficacy of thiopurines. In particular, cells indicated that NUDT15 ablation potentiated induction of increasing evidence suggests an association between the the DNA damage checkpoint and cancer cell death by 6-thio- NUDT15 missense variant, R139C, and thiopurine sensitivity. guanine. Taken together, our results defined how NUDT15 In this study, we elucidated the role of NUDT15 and NUDT15 limits thiopurine efficacy and how genetic ablation via the R139C in thiopurine metabolism. In vitro and cellular results R139C missense mutation confers sensitivity to thiopurine argued that 6-thio-dGTP and 6-thio-GTP are favored substrates treatment in patients. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
GIGANTUS1 (GTS1), a Member of Transducin/WD40 Protein
Gachomo et al. BMC Plant Biology 2014, 14:37 http://www.biomedcentral.com/1471-2229/14/37 RESEARCH ARTICLE Open Access GIGANTUS1 (GTS1), a member of Transducin/WD40 protein superfamily, controls seed germination, growth and biomass accumulation through ribosome-biogenesis protein interactions in Arabidopsis thaliana Emma W Gachomo1,2†, Jose C Jimenez-Lopez3,4†, Lyla Jno Baptiste1 and Simeon O Kotchoni1,2* Abstract Background: WD40 domains have been found in a plethora of eukaryotic proteins, acting as scaffolding molecules assisting proper activity of other proteins, and are involved in multi-cellular processes. They comprise several stretches of 44-60 amino acid residues often terminating with a WD di-peptide. They act as a site of protein-protein interactions or multi-interacting platforms, driving the assembly of protein complexes or as mediators of transient interplay among other proteins. In Arabidopsis, members of WD40 protein superfamily are known as key regulators of plant-specific events, biologically playing important roles in development and also during stress signaling. Results: Using reverse genetic and protein modeling approaches, we characterize GIGANTUS1 (GTS1), a new member of WD40 repeat protein in Arabidopsis thaliana and provide evidence of its role in controlling plant growth development. GTS1 is highly expressed during embryo development and negatively regulates seed germination, biomass yield and growth improvement in plants. Structural modeling analysis suggests that GTS1 folds into a β-propeller with seven pseudo symmetrically arranged blades around a central axis. Molecular docking analysis shows that GTS1 physically interacts with two ribosomal protein partners, a component of ribosome Nop16, and a ribosome-biogenesis factor L19e through β-propeller blade 4 to regulate cell growth development. -
S41467-020-18249-3.Pdf
ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible. -
Homozygous Mutation in NUDT15 in Childhood Acute Lymphoblastic Leukemia with Increased Susceptibility to Mercaptopurine Toxicity: a Case Report
EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: 4285-4288, 2019 Homozygous mutation in NUDT15 in childhood acute lymphoblastic leukemia with increased susceptibility to mercaptopurine toxicity: A case report JUAN CHENG1*, HAO ZHANG1*, HAI-ZHEN MA1 and JUAN LI2 Departments of 1Hematology and 2Central Laboratory, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China Received April 11, 2018; Accepted March 13, 2019 DOI: 10.3892/etm.2019.7434 Abstract. As an essential component of consolidation and of induction therapy, and the different expression of minimal maintenance therapy for acute lymphoblastic leukemia (ALL), residual disease (MRD) (3,4). Newly diagnosed patients mercaptopurine (6-MP) causes critical myelosuppression. The with ALL require a rigorous, standardized and long‑course current study aimed to clarify the reasons for severe myelosup- chemotherapy treatment strategy, which includes induction, pression and significant hyperpigmentationin a patient with ALL consolidation, intensification and maintenance therapy (5). that received consolidation therapy. The present study performed Additionally, stratification of treatment intensity is based on patient NUDT15 testing with fluorescence in situ hybridization the risk stratification of leukemic blasts identified in ALL (4). and whole‑exome sequencing. The results revealed that the The disease-free survival and the curative rate have greatly patient was a homozygous carrier (415C>T, TT) for rs116855232 improved with improved diagnosis and treatment regi- (NUDT15). The dose of 6‑MP was adjusted down from 30%, mens (6). However, treatment interruption or discontinuation with the patient receiving maintenance therapy at 8% of the due to hematopoietic toxicity is a common adverse event and recommended dose. The homozygous mutant (TT genotype) results in a higher risk of relapse (7). -
Dissertation
Regulation of gene silencing: From microRNA biogenesis to post-translational modifications of TNRC6 complexes DISSERTATION zur Erlangung des DOKTORGRADES DER NATURWISSENSCHAFTEN (Dr. rer. nat.) der Fakultät Biologie und Vorklinische Medizin der Universität Regensburg vorgelegt von Johannes Danner aus Eggenfelden im Jahr 2017 Das Promotionsgesuch wurde eingereicht am: 12.09.2017 Die Arbeit wurde angeleitet von: Prof. Dr. Gunter Meister Johannes Danner Summary ‘From microRNA biogenesis to post-translational modifications of TNRC6 complexes’ summarizes the two main projects, beginning with the influence of specific RNA binding proteins on miRNA biogenesis processes. The fate of the mature miRNA is determined by the incorporation into Argonaute proteins followed by a complex formation with TNRC6 proteins as core molecules of gene silencing complexes. miRNAs are transcribed as stem-loop structured primary transcripts (pri-miRNA) by Pol II. The further nuclear processing is carried out by the microprocessor complex containing the RNase III enzyme Drosha, which cleaves the pri-miRNA to precursor-miRNA (pre-miRNA). After Exportin-5 mediated transport of the pre-miRNA to the cytoplasm, the RNase III enzyme Dicer cleaves off the terminal loop resulting in a 21-24 nt long double-stranded RNA. One of the strands is incorporated in the RNA-induced silencing complex (RISC), where it directly interacts with a member of the Argonaute protein family. The miRNA guides the mature RISC complex to partially complementary target sites on mRNAs leading to gene silencing. During this process TNRC6 proteins interact with Argonaute and recruit additional factors to mediate translational repression and target mRNA destabilization through deadenylation and decapping leading to mRNA decay. -
Cardiovascular & Hematological Agents Inmedicinal Chemistry
Send Orders for Reprints to [email protected] 23 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2017, 15, 23-30 REVIEW ARTICLE ISSN: 1871-5257 eISSN: 1875-6182 Cardiovascular & Hematological Agents Thiopurine S-Methyltransferase as a Pharmacogenetic Biomarker: Signif- icance of Testing and Review of Major Methods The journal for current and in-depth reviews on Cardiovascular & Hematological Agents Chingiz Asadov*, Gunay Aliyeva and Kamala Mustafayeva Department of Hematopoietic Pathologies, Institute of Hematology and Blood Transfusion, Baku, Azerbaijan Abstract: Background: Thiopurine S-methyltransferase (TPMT) enzyme metabolizes thiopurine drugs which are widely used in various disciplines as well as in leukemias. Individual enzyme activity varies depending on the genetic polymorphisms of TPMT gene located at chromosome 6. Up to 14% of population is known to have a decreased enzyme activity, and if treated with standard doses of thiopurines, these individuals are at a high risk of severe Adverse Drug Reactions (ADR) as myelosuppression, gastrointestinal intolerance, pancreati- A R T I C L E H I S T O R Y tis and hypersensitivity. However, TPMT-deficient patients can successfully be treated with decreased thiopu- Received: November 30, 2016 rine doses if enzyme status is identified by a prior testing. TPMT status identification is a pioneering experience Revised: February 25, 2017 Accepted: March 21, 2017 in application of pharmacogenetic testing in clinical settings. 4 TPMT (*2, *3A, *3B, *3C) alleles are known to account for 80-95% of a decreased enzyme activity, and therefore, identifying the presence of these alleles sup- DOI: 10.2174/1871525715666170529091921 ported by phenotypic measurement of the enzyme activity can reveal patient’s TPMT status. -
The Roles of the Exoribonucleases DIS3L2 and XRN1 in Human Disease
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Sussex Research Online The roles of the exoribonucleases DIS3L2 and XRN1 in human disease. Amy L. Pashler1, Ben Towler1, Christopher I. Jones2 and Sarah F. Newbury* 1Brighton and Sussex Medical School, Medical Research building, University of Sussex, Falmer, Brighton, BN1 9PS, U.K. 2Brighton and Sussex Medical School, Department of Primary Care and Public Health, University of Brighton, Falmer, Brighton, BN1 9PH, U.K. *Corresponding author: [email protected] +44 (0)1273 877874 Abstract RNA degradation is a vital post-transcriptional process which ensures that transcripts are maintained at the correct level within the cell. DIS3L2 and XRN1 are conserved exoribonucleases which are critical for the degradation of cytoplasmic RNAs. Although the molecular mechanisms of RNA degradation by DIS3L2 and XRN1 have been well studied, less is known about their specific roles in development of multicellular organisms or human disease. This review focusses on the roles of DIS3L2 and XRN1 in the pathogenesis of human disease, particularly in relation to phenotypes seen in model organisms. The known diseases associated with loss of activity of DIS3L2 and XRN1 are discussed, together with possible mechanisms and cellular pathways leading to these disease conditions. Key words: RNA stability, RNA degradation, human disease, virus-host interactions, XRN1, DIS3L2 Abbreviations used: UTR, untranslated region; HCV, Hepatitis C virus; sfRNA, small flaviviral non- coding RNA; mRNA, messenger RNA; miRNA, microRNA. Introduction Ribonucleases are key enzymes involved in the control of mRNA stability, which is crucially important in maintaining RNA transcripts at the correct levels within cells. -
Xrn1 - a Major Mrna Synthesis and Decay Factor
bioRxiv preprint doi: https://doi.org/10.1101/2021.04.01.437949; this version posted April 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. RNA-controlled nucleocytoplasmic shuttling of mRNA decay factors regulates mRNA synthesis and initiates a novel mRNA decay pathway Running title: Cytoplasmic mRNA decay begins in the nucleus Shiladitya Chattopadhyay1, Jose Garcia-Martinez2, Gal Haimovich1,3, Aya Khwaja1, Oren Barkai1, Ambarnil Ghosh4, Silvia Gabriela Chuarzman5, Maya Schuldiner5, Ron Elran1, Miriam Rosenberg1, Katherine Bohnsack6, Markus Bohnsack6, Jose E Perez-Ortin2, Mordechai Choder1* 1Department of Molecular Microbiology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel. 2Instituto de Biotecnología y Biomedicina (Biotecmed), Universitat de València ; Burjassot, Valencia, 46100, Spain. 3current address:Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel. 4UCD Conway Institute of Biomolecular & Biomedical Research, Dublin, Ireland. 5Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel 6Institute for Molecular Biology, University Medical Center Göttingen Georg-August- University, Göttingen, Germany Göttingen Centre for Molecular Biosciences, Georg-August- University, Göttingen, Germany *Corresponding Author: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2021.04.01.437949; this version posted April 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. -
Massively Parallel Variant Characterization Identifies NUDT15 Alleles Associated with Thiopurine Toxicity
Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity Chase C. Suitera, Takaya Moriyamaa, Kenneth A. Matreyekb, Wentao Yanga, Emma Rose Scalettic,d, Rina Nishiia, Wenjian Yanga, Keito Hoshitsukia, Minu Singhe, Amita Trehane, Chris Parisha, Colton Smitha, Lie Lia, Deepa Bhojwanif, Liz Y. P. Yueng, Chi-kong Lih, Chak-ho Lii, Yung-li Yangj, Gareth J. Walkerk,l, James R. Goodhandk,l, Nicholas A. Kennedyk,l, Federico Antillon Klussmannm,n, Smita Bhatiao, Mary V. Rellinga, Motohiro Katop, Hiroki Horiq, Prateek Bhatiae, Tariq Ahmadk,l, Allen E. J. Yeohr,s, Pål Stenmarkc,d, Douglas M. Fowlerb,t,u, and Jun J. Yanga,1 aDepartment of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN 38105; bDepartment of Genome Sciences, University of Washington, Seattle, WA 98195; cDepartment of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden; dDepartment of Experimental Medical Science,Lund University, 221 00 Lund, Sweden; eDepartment of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education & Research, 160012 Chandigarh, India; fDepartment of Pediatrics, Children’s Hospital of Los Angeles, Los Angeles, CA 90027; gDepartment of Pathology, Hong Kong Children’s Hospital, Hong Kong; hDepartment of Paediatrics, The Chinese University of Hong Kong, Hong Kong; iDepartment of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong; jDepartment of Laboratory Medicine and Pediatrics, -
Fanconi Anemia Protein FANCI Functions in Ribosome Biogenesis
Fanconi anemia protein FANCI functions in ribosome biogenesis Samuel B. Sondallea, Simonne Longerichb,1, Lisa M. Ogawab, Patrick Sungb,c, and Susan J. Basergaa,b,c,2 aDepartment of Genetics, Yale School of Medicine, New Haven, CT 06520; bDepartment of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06520; and cDepartment of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520 Edited by Joseph G. Gall, Carnegie Institution of Washington, Baltimore, MD, and approved December 28, 2018 (received for review July 8, 2018) Fanconi anemia (FA) is a disease of DNA repair characterized by bone responsible for the transcription of pre-ribosomal RNA (pre- marrow failure and a reduced ability to remove DNA interstrand rRNA) (33). The clear phenotypic overlap between FA and cross-links. Here, we provide evidence that the FA protein FANCI also bone marrow failure ribosomopathies and the connection between functions in ribosome biogenesis, the process of making ribosomes BRCA1 (FANCS) and RNAPI suggest a possible connection be- that initiates in the nucleolus. We show that FANCI localizes to the tween FA and defects in ribosome biogenesis. nucleolus and is functionally and physically tied to the transcription The process of making ribosomes in eukaryotes, termed ri- of pre-ribosomal RNA (pre-rRNA) and to large ribosomal subunit bosome biogenesis, initiates in the large nonmembrane-bound (LSU) pre-rRNA processing independent of FANCD2. While FANCI is nuclear organelle, the nucleolus (NO) (34, 35). In the NO, tan- known to be monoubiquitinated when activated for DNA repair, we dem repeats of ribosomal DNA (rDNA) (36) are transcribed by find that it is predominantly in the deubiquitinated state in the RNAPI, which generates a long pre-rRNA (37). -
Sumoylation of PES1 Upregulates Its Stability and Function Via Inhibiting Its Ubiquitination
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 31 Research Paper SUMOylation of PES1 upregulates its stability and function via inhibiting its ubiquitination Shujing Li1, Miao Wang1, Xinjian Qu2, Zhaowei Xu1, Yangyang Yang1, Qiming Su2, Huijian Wu1,2 1School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China 2School of Life Science and Medicine, Dalian University of Technology, Panjin, China Correspondence to: Huijian Wu, email: [email protected] Keywords: PES1, SUMOylation, breast cancer, ubiquitination Received: July 21, 2015 Accepted: June 15, 2016 Published: July 08, 2016 ABSTRACT PES1 is a component of the PeBoW complex, which is required for the maturation of 28S and 5.8S ribosomal RNAs, as well as for the formation of the 60S ribosome. Deregulation of ribosomal biogenesis can contribute to carcinogenesis. In this study, we showed that PES1 could be modified by the small ubiquitin-like modifier (SUMO) SUMO-1, SUMO-2 and SUMO-3, and SUMOylation of PES1 was stimulated by estrogen (E2). One major SUMOylation site (K517) was identified in the C-terminal Glu-rich domain of PES1. Substitution of K517 with arginine abolished the SUMOylation of PES1. SUMOylation also stabilized PES1 through inhibiting its ubiquitination. In addition, PES1 SUMOylation positively regulated the estrogen signaling pathway. SUMOylation enhanced the ability of PES1 to promote estrogen receptor α (ERα)- mediated transcription by increasing the stability of ERα, both in the presence and absence of E2. Moreover, SUMOylation of PES1 also increased the proportion of S-phase cells in the cell cycle and promoted the proliferation of breast cancer cells both in vitro and in vivo.