Modification of Topoisomerase Genes Copy Number in Newly Diagnosed
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Transcription-Induced DNA Double Strand Breaks: Both Oncogenic Force and Potential Therapeutic Target?
Published OnlineFirst March 8, 2011; DOI: 10.1158/1078-0432.CCR-10-2044 Clinical Cancer Molecular Pathways Research Transcription-Induced DNA Double Strand Breaks: Both Oncogenic Force and Potential Therapeutic Target? Michael C. Haffner, Angelo M. De Marzo, Alan K. Meeker, William G. Nelson, and Srinivasan Yegnasubramanian Abstract An emerging model of transcriptional activation suggests that induction of transcriptional programs, for instance by stimulating prostate or breast cells with androgens or estrogens, respectively, involves the formation of DNA damage, including DNA double strand breaks (DSB), recruitment of DSB repair proteins, and movement of newly activated genes to transcription hubs. The DSB can be mediated by the class II topoisomerase TOP2B, which is recruited with the androgen receptor and estrogen receptor to regulatory sites on target genes and is apparently required for efficient transcriptional activation of these genes. These DSBs are recognized by the DNA repair machinery triggering the recruitment of repair proteins such as poly(ADP-ribose) polymerase 1 (PARP1), ATM, and DNA-dependent protein kinase (DNA-PK). If illegitimately repaired, such DSBs can seed the formation of genomic rearrangements like the TMPRSS2- ERG fusion oncogene in prostate cancer. Here, we hypothesize that these transcription-induced, TOP2B- mediated DSBs can also be exploited therapeutically and propose that, in hormone-dependent tumors like breast and prostate cancers, a hormone-cycling therapy, in combination with topoisomerase II poisons or inhibitors of the DNA repair components PARP1 and DNA-PK, could overwhelm cancer cells with transcription-associated DSBs. Such strategies may find particular utility in cancers, like prostate cancer, which show low proliferation rates, in which other chemotherapeutic strategies that target rapidly proliferating cells have had limited success. -
Targeting Topoisomerase I in the Era of Precision Medicine Anish Thomas and Yves Pommier
Published OnlineFirst June 21, 2019; DOI: 10.1158/1078-0432.CCR-19-1089 Review Clinical Cancer Research Targeting Topoisomerase I in the Era of Precision Medicine Anish Thomas and Yves Pommier Abstract Irinotecan and topotecan have been widely used as including the indenoisoquinolines LMP400 (indotecan), anticancer drugs for the past 20 years. Because of their LMP776 (indimitecan), and LMP744, and on tumor- selectivity as topoisomerase I (TOP1) inhibitors that trap targeted delivery TOP1 inhibitors using liposome, PEGyla- TOP1 cleavage complexes, camptothecins are also widely tion, and antibody–drug conjugates. We also address how used to elucidate the DNA repair pathways associated with tumor-specific determinants such as homologous recombi- DNA–protein cross-links and replication stress. This review nation defects (HRD and BRCAness) and Schlafen 11 summarizes the basic molecular mechanisms of action (SLFN11) expression can be used to guide clinical appli- of TOP1 inhibitors, their current use, and limitations cation of TOP1 inhibitors in combination with DNA dam- as anticancer agents. We introduce new therapeutic strate- age response inhibitors including PARP, ATR, CHEK1, and gies based on novel TOP1 inhibitor chemical scaffolds ATM inhibitors. Introduction DNA structures such as plectonemes, guanosine quartets, R-loops, and DNA breaks (reviewed in ref. 1). Humans encodes six topoisomerases, TOP1, TOP1MT, TOP2a, TOP2b, TOP3a, and TOP3b (1) to pack and unpack the approx- imately 2 meters of DNA that needs to be contained in the nucleus Anticancer TOP1 Inhibitors Trap TOP1CCs whose diameter (6 mm) is approximately 3 million times smaller. as Interfacial Inhibitors Moreover, the genome is organized in chromosome loops and the separation of the two strands of DNA during transcription and The plant alkaloid camptothecin and its clinical derivatives, replication generate torsional stress and supercoils that are topotecan and irinotecan (Fig. -
Single-Nuclei RNA-Seq on Human Retinal Tissue Provides Improved Transcriptome Profiling
ARTICLE https://doi.org/10.1038/s41467-019-12917-9 OPEN Single-nuclei RNA-seq on human retinal tissue provides improved transcriptome profiling Qingnan Liang 1,2,3,9, Rachayata Dharmat1,2,8,9, Leah Owen4, Akbar Shakoor4, Yumei Li1, Sangbae Kim1, Albert Vitale4, Ivana Kim4, Denise Morgan4,5, Shaoheng Liang 6, Nathaniel Wu1, Ken Chen 6, Margaret M. DeAngelis4,5,7* & Rui Chen1,2,3* Single-cell RNA-seq is a powerful tool in decoding the heterogeneity in complex tissues by 1234567890():,; generating transcriptomic profiles of the individual cell. Here, we report a single-nuclei RNA- seq (snRNA-seq) transcriptomic study on human retinal tissue, which is composed of mul- tiple cell types with distinct functions. Six samples from three healthy donors are profiled and high-quality RNA-seq data is obtained for 5873 single nuclei. All major retinal cell types are observed and marker genes for each cell type are identified. The gene expression of the macular and peripheral retina is compared to each other at cell-type level. Furthermore, our dataset shows an improved power for prioritizing genes associated with human retinal dis- eases compared to both mouse single-cell RNA-seq and human bulk RNA-seq results. In conclusion, we demonstrate that obtaining single cell transcriptomes from human frozen tissues can provide insight missed by either human bulk RNA-seq or animal models. 1 HGSC, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston 77030 TX, USA. 3 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA. -
Gene Amplification
Europaisches Patentamt J) European Patent Office © Publication number: 0 319 206 Office europeen des brevets A2 EUROPEAN PATENT APPLICATION © C12N Application number: 88311183.3 © int. ci."; 15/00 , C12N 5/00 © Date of filing: 25.11.88 © Priority: 30.11.87 US 126436 © Applicant: CODON CORPORATION 213 East Grand Avenue © Date of publication of application: South San Francisco California 94025(CA) 07.06.89 Bulletin 89/23 © Inventor: Colby, Wendy W. © Designated Contracting States: 2018 Lyon Avenue AT BE CH DE FR GB IT LI LU NL SE Belmont California 94002(US) Inventor: Morser, Michael J. 3964 - 20th Street San Francisco California 94114(US) Inventor: Cashion, Linda M. 219 Kelton Avenue San Carlos California 94070(US) © Representative: Thomson, Paul Anthony et al Potts, Kerr & Co. 15, Hamilton Square Birkenhead Merseyside L41 6BR(GB) © Gene amplification. © Improved means are provided for obtaining enhanced production of proteins encoded by structural genes of interest in a host based on transfecting the host with an expression vector comprising a wild-type amplifiable gene and the predetermined structural gene. The host is typically not complemented by the amplifiable gene product. If desired, another selection marker may be utilized to select a desired population of cells prior to the amplification. CM < CO o CM G) i— CO o CL LLI <erox Copy Centre EP 0 319 206 A2 GENE AMPLIFICATION Field of the Invention This invention relates generally to improved recombinant DNA techniques and the increased expression 5 of mammalian polypeptides in genetically engineered eukaryotic cells. More specifically, the invention relates to improved methods of selecting transfected cells and further, to methods of gene amplification resulting in the expression of predetermined gene products at very high levels. -
Prediction-Based Highly Sensitive CRISPR Off
bioRxiv preprint doi: https://doi.org/10.1101/2019.12.31.889626; this version posted December 31, 2019. 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 4.0 International license. Prediction-based highly sensitive CRISPR off- target validation using target-specific DNA enrichment Seung-Hun Kang1,6, Wi-jae Lee1,8, Ju-Hyun An1, Jong-Hee Lee2, Young-Hyun Kim2,3, Hanseop Kim1,7, Yeounsun Oh1,9, Young-Ho Park1, Yeung Bae Jin2, Bong-Hyun Jun8, Junho K Hur4,5,#, Sun-Uk Kim1,3,# and Seung Hwan Lee2,# 1Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Korea 2National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Korea 3Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea 4Department of Pathology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea 5Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea 6Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea 7School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea 8Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Korea 9Division of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Republic of Korea #Correspondence: [email protected], [email protected], [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2019.12.31.889626; this version posted December 31, 2019. -
DNA Topoisomerase 1 and 2A Function As Oncogenes in Liver Cancer and May Be Direct Targets of Nitidine Chloride
INTERNATIONAL JOURNAL OF ONCOLOGY 53: 1897-1912, 2018 DNA topoisomerase 1 and 2A function as oncogenes in liver cancer and may be direct targets of nitidine chloride LI-MIN LIU1*, DAN-DAN XIONG2*, PENG LIN3, HONG YANG3, YI-WU DANG2 and GANG CHEN2 1Department of Toxicology, College of Pharmacy, Guangxi Medical University; 2Department of Pathology; 3Ultrasonics Division, Radiology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China Received March 16, 2018; Accepted July 31, 2018 DOI: 10.3892/ijo.2018.4531 Abstract. The aim of the present study was to determine the role of patients with LC and for identification of high-risk cases, of topoisomerase 1 (TOP1) and topoisomerase 2A (TOP2A) thereby optimizing individual treatment management. More in liver cancer (LC), and to investigate the inhibitory effect importantly, the findings support TOP1 and TOP2A as poten- of nitidine chloride (NC) on these two topoisomerases. tial drug targets of NC for the treatment of LC. Immunohistochemistry (IHC) staining and microarray or RNA sequencing data mining showed markedly higher expression Introduction of TOP1 and TOP2A at the protein and mRNA levels in LC tissues compared with that in control non-tumor tissues. The Liver cancer (LC) is the second main cause of cancer-associated prognostic values of TOP1 and TOP2A expression were also mortality threatening global public health, with hepatocellular estimated based on data from The Cancer Genome Atlas. The carcinoma (HCC) being the main histopathological subtype (1,2). elevated expression levels of TOP1 and TOP2A were closely In the United States, the American Cancer Society projects that associated with poorer overall survival and disease-free >30,000 patients will succumb to LC in 2018 (3). -
Associated with Past Or Ongoing Infection with a Hepadnavirus (Hepatoceflular Carcinoma/N-Myc/Retroposon) CATHERINE TRANSY*, GENEVIEVE FOUREL*, WILLIAM S
Proc. Nati. Acad. Sci. USA Vol. 89, pp. 3874-3878, May 1992 Biochemistry Frequent amplification of c-mnc in ground squirrel liver tumors associated with past or ongoing infection with a hepadnavirus (hepatoceflular carcinoma/N-myc/retroposon) CATHERINE TRANSY*, GENEVIEVE FOUREL*, WILLIAM S. ROBINSONt, PIERRE TIOLLAIS*, PATRICIA L. MARIONt, AND MARIE-ANNICK BUENDIA*t *Unit6 de Recombinaison et Expression Gdndtique, Institut National de la Santd et de la Recherche Mddicale U163, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris, Cedex 15, France; and tDivision of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 Communicated by Andre Lwoff, January 23, 1992 (received for review November 5, 1991) ABSTRACT Persistent infection with hepatitis B virus HCC through distinct and perhaps cooperative mechanisms. (HBV) is a major cause of hepatoceliular carcinoma (HCC) in However, the cellular factors involved in virally induced humans. HCC has also been observed in animals chronically oncogenesis remain largely unknown. infected with two other hepadnaviruses: ground squirrel hep- In this regard, hepadnaviruses infecting lower animals, atitis virus (GSHV) and woodchuck hepatitis virus (WHV). A such as the woodchuck hepatitis virus (WHV) and the ground distinctive feature of WHV is the early onset of woodchuck squirrel hepatitis virus (GSHV), represent interesting mod- tumors, which may be correlated with a direct role of the virus els. Chronic infection with WHV has been found to be as an insertional mutagen of myc genes: c-myc, N-myc, and associated with a high incidence and a rapid onset of HCCs predominantly the woodchuck N-myc2 retroposon. In the in naturally infected woodchucks (11), and the oncogenic present study, we searched for integrated GSHV DNA and capacity of the virus has been further demonstrated in genetic alterations ofmyc genes in ground squirrel HCCs. -
Quantitation of C-Myc Gene Amplification by a Competitive PCR Assay System
Downloaded from genome.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Quantitation of c-myc Gene Amplification by a Competitive PCR Assay System Seth P. Harlow and Carleton C. Stewart Departments of Surgical Oncology and Flow Cytometry, Roswell Park Cancer Institute, Buffalo, New York 14263 Gene amplification is a common Gene amplification, particularly am- being possible. A number of variables, event in the progression of human plification of the growth-promoting however, must be accounted for to de- cancers. The detection and quantita- proto-oncogenes, is a common event in termine the true gene amplification level tion of certain amplified oncogenes the progression of many human can- in a population of cells. These include has been shown to have prognostic cers. (~ Detection and quantitation of cell number, cell cycle phase (cells in G 2 importance in certain human malig- certain specific amplified genes may or mitosis will have twice the gene cop- nancies. A method is described that have the potential for predicting patient ies as cells in G O or G1), and chromo- utilizes the principles of competitive outcome or response to therapy for a some ploidy (genes on aneuploid chro- PCR for quantitation of the c-mu number of different human tumor mosomes generally are not considered gene copy number in relation to the types. (2'3) Recently, a number of meth- amplified). To account for all of these copy number of a reference gene (tis- ods have been described to accomplish variables, quantitation of an internal sue plasminogen activator It-PAl this goal by a variety of techniques (4-6~ control or reference gene has been used gene) located on the same chromo- differing from the standard Southern routinely in Southern techniques. -
The Role of Sumoylation of DNA Topoisomerase Iiα C-Terminal Domain in the Regulation of Mitotic Kinases In
SUMOylation at the centromere: The role of SUMOylation of DNA topoisomerase IIα C-terminal domain in the regulation of mitotic kinases in cell cycle progression. By Makoto Michael Yoshida Submitted to the graduate degree program in the Department of Molecular Biosciences and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ________________________________________ Chairperson: Yoshiaki Azuma, Ph.D. ________________________________________ Roberto De Guzman, Ph.D. ________________________________________ Kristi Neufeld, Ph.D. _________________________________________ Berl Oakley, Ph.D. _________________________________________ Blake Peterson, Ph.D. Date Defended: July 12, 2016 The Dissertation Committee for Makoto Michael Yoshida certifies that this is the approved version of the following dissertation: SUMOylation at the centromere: The role of SUMOylation of DNA topoisomerase IIα C-terminal domain in the regulation of mitotic kinases in cell cycle progression. ________________________________________ Chairperson: Yoshiaki Azuma, Ph.D. Date approved: July 12, 2016 ii ABSTRACT In many model systems, SUMOylation is required for proper mitosis; in particular, chromosome segregation during anaphase. It was previously shown that interruption of SUMOylation through the addition of the dominant negative E2 SUMO conjugating enzyme Ubc9 in mitosis causes abnormal chromosome segregation in Xenopus laevis egg extract (XEE) cell-free assays, and DNA topoisomerase IIα (TOP2A) was identified as a substrate for SUMOylation at the mitotic centromeres. TOP2A is SUMOylated at K660 and multiple sites in the C-terminal domain (CTD). We sought to understand the role of TOP2A SUMOylation at the mitotic centromeres by identifying specific binding proteins for SUMOylated TOP2A CTD. Through affinity isolation, we have identified Haspin, a histone H3 threonine 3 (H3T3) kinase, as a SUMOylated TOP2A CTD binding protein. -
Sumoylation of DNA Topoisomerase Iiα Regulates Histone H3 Kinase Haspin and H3 Phosphorylation in Mitosis
JCB: Article SUMOylation of DNA topoisomerase IIα regulates histone H3 kinase Haspin and H3 phosphorylation in mitosis Makoto M. Yoshida,1 Lily Ting,2 Steven P. Gygi,2 and Yoshiaki Azuma1 1Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045 2Department of Cell Biology, Harvard Medical School, Boston, MA 02115 DNA topoisomerase II (TOP2) plays a pivotal role in faithful chromosome separation through its strand-passaging ac- tivity that resolves tangled genomic DNA during mitosis. Additionally, TOP2 controls progression of mitosis by activating cell cycle checkpoints. Recent work showed that the enzymatically inert C-terminal domain (CTD) of TOP2 and its post- translational modification are critical to this checkpoint regulation. However, the molecular mechanism has not yet been determined. By using Xenopus laevis egg extract, we found that SUMOylation of DNA topoisomerase IIα (TOP2A) CTD Downloaded from regulates the localization of the histone H3 kinase Haspin and phosphorylation of histone H3 at threonine 3 at the cen- tromere, two steps known to be involved in the recruitment of the chromosomal passenger complex (CPC) to kinetochores in mitosis. Robust centromeric Haspin localization requires SUMOylated TOP2A CTD binding activity through SUMO- interaction motifs and the phosphorylation of Haspin. We propose a novel mechanism through which the TOP2 CTD regulates the CPC via direct interaction with Haspin at mitotic centromeres. jcb.rupress.org Introduction Cell stage–specific kinases are important for the progression of the centromere through the activity of histone H3 kinase Haspin, on September 20, 2017 mitosis. These kinases play a role in specific pathways to en- which phosphorylates histone H3 at threonine 3 (H3T3) for its sure that chromosomes segregate properly to daughter cells to direct interaction with the BIR domain of Survivin (Kelly et prevent aneuploidy. -
Retrotransposon-Mediated Host Gene Capture, Complementation
1 Cascade evolution in poxviruses: retrotransposon-mediated host gene capture, 2 complementation and recombination 3 4 M. Julhasur Rahman1, Sherry L. Haller2, Jie Li3, Greg Brennan1 and Stefan Rothenburg1* 5 6 1 School of Medicine, University of California Davis, Department of Medial Microbiology and 7 Immunology, Davis, CA 95616, USA 8 2 University of Texas Medical Branch at Galveston, Department of Microbiology and 9 Immunology, Galveston, TX 77555, USA 10 3 Genome Center, University of California Davis, Davis, CA 95616, USA 11 *correspondence: [email protected]. ORCID iD:0000-0002-2525-8230 12 13 14 Keywords: horizontal gene transfer; LINE-1; retrotransposons; poxvirus; evolution, PKR; E3L 15 1 16 Abstract 17 18 There is ample phylogenetic evidence that many critical virus functions, like immune evasion, 19 evolved by the acquisition of genes from their hosts by horizontal gene transfer (HGT). However, 20 the lack of an experimental system has prevented a mechanistic understanding of this process. We 21 developed a model to elucidate the mechanisms of HGT into poxviruses. All identified gene 22 capture events showed signatures of LINE-1-mediated retrotransposition. Integrations occurred 23 across the genome, in some cases knocking out essential viral genes. These essential gene 24 knockouts were rescued through a process of complementation by the parent virus followed by 25 non-homologous recombination to generate a single competent virus. This work links multiple 26 evolutionary mechanisms into one adaptive cascade and identifies host retrotransposons as major 27 drivers for virus evolution. 28 29 30 2 31 Introduction 32 33 Horizontal gene transfer (HGT) is the transmission of genetic material between different 34 organisms. -
Differential Expression of Multiple Disease-Related Protein Groups
brain sciences Article Differential Expression of Multiple Disease-Related Protein Groups Induced by Valproic Acid in Human SH-SY5Y Neuroblastoma Cells 1,2, 1, 1 1 Tsung-Ming Hu y, Hsiang-Sheng Chung y, Lieh-Yung Ping , Shih-Hsin Hsu , Hsin-Yao Tsai 1, Shaw-Ji Chen 3,4 and Min-Chih Cheng 1,* 1 Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien 98142, Taiwan; [email protected] (T.-M.H.); [email protected] (H.-S.C.); [email protected] (L.-Y.P.); fi[email protected] (S.-H.H.); [email protected] (H.-Y.T.) 2 Department of Future Studies and LOHAS Industry, Fo Guang University, Jiaosi, Yilan County 26247, Taiwan 3 Department of Psychiatry, Mackay Medical College, New Taipei City 25245, Taiwan; [email protected] 4 Department of Psychiatry, Taitung Mackay Memorial Hospital, Taitung County 95064, Taiwan * Correspondence: [email protected]; Tel.: +886-3888-3141 (ext. 475) These authors contributed equally to this work. y Received: 10 July 2020; Accepted: 8 August 2020; Published: 12 August 2020 Abstract: Valproic acid (VPA) is a multifunctional medication used for the treatment of epilepsy, mania associated with bipolar disorder, and migraine. The pharmacological effects of VPA involve a variety of neurotransmitter and cell signaling systems, but the molecular mechanisms underlying its clinical efficacy is to date largely unknown. In this study, we used the isobaric tags for relative and absolute quantitation shotgun proteomic analysis to screen differentially expressed proteins in VPA-treated SH-SY5Y cells. We identified changes in the expression levels of multiple proteins involved in Alzheimer’s disease, Parkinson’s disease, chromatin remodeling, controlling gene expression via the vitamin D receptor, ribosome biogenesis, ubiquitin-mediated proteolysis, and the mitochondrial oxidative phosphorylation and electron transport chain.