DOCSLIB.ORG

Candidate Synthetic Lethality Partners to PARP Inhibitors in the Treatment of Ovarian Clear Cell Cancer (Review)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Candidate Synthetic Lethality Partners to PARP Inhibitors in the Treatment of Ovarian Clear Cell Cancer (Review) BIOMEDICAL REPORTS 7: 391-399, 2017 Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer (Review) NAOKI KAWAHARA, KENJI OGAWA, MIKA NAGAYASU, MAI KIMURA, YOSHIKAZU SASAKI and HIROSHI KOBAYASHI Department of Obstetrics and Gynecology, Nara Medical University, Nara 634-8522, Japan Received August 18, 2017; Accepted September 14, 2017 DOI: 10.3892/br.2017.990 Abstract. Inhibitors of poly(ADP-ribose) polymerase Contents (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 1. Introduction mutations. Ovarian clear cell cancer (CCC), a subset of 2. Systematic review of the literature using electronic ovarian cancer, often appears as low-stage disease with search in the PubMed/Medline databases a higher incidence among Japanese. Advanced CCC is 3. Future opportunities in the use of PARP inhibition in CCC highly aggressive with poor patient outcome. The aim of 4. Candidate mutated genes for enhancing the therapeutic the present study was to determine the potential synthetic ratio achieved by PARP inhibitors in CCC (Table IA). lethality gene pairs for PARP inhibitions in patients with 5. Upregulated genes enhancing synthetic lethality of CCC through virtual and biological screenings as well as PARP inhibitors in CCC (Table IB) clinical studies. We conducted a literature review for puta- 6. Synthetic lethal gene partners based on tive PARP sensitivity genes that are associated with the chemo resi stance-related genes in CCC (Table IC) CCC pathophysiology. Previous studies identified a variety 7. Discussion of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle 1. Introduction checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used Epithelial ovarian cancer is an advanced and metastatic disease as biomarkers or therapeutic targets for PARP inhibition. at presentation and responsible for over 50% of mortalities BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, worldwide in female genital malignancies (1). The current DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and standard treatment strategy for ovarian cancer is cytoreductive PTEN were considered as candidate genes for synthetic surgery followed by platinum- and taxane-based combination lethality gene partners for PARP interactions. When chemotherapy. Approximately 75% of patients with advanced considering the biological background underlying PARP ovarian cancer ultimately suffer from tumor recurrence with inhibition, we hypothesized that PARP inhibitors would 20% of these patients having resistant disease (1). High rates of be a novel synthetic lethal therapeutic approach for CCC recurrence and low chemosensitivity are the two main factors tumors harboring homologous recombination deficiency that account for poor prognosis of this disease. Epithelial and activating oncogene mutations. The results showed that ovarian cancer is a highly heterogeneous disease characterized the majority of CCC tumors appear to have indicators of by at least two different subtypes, including distinct clinico- DNA repair dysfunction similar to those in BRCA-mutation pathologic characteristics, molecular pathogenesis, responses carriers, suggesting the possible utility of PARP inhibitors to treatment and patient prognosis (2). Each subtype also in a subset of CCC. contains a distinct gene mutation profile and exhibits varied gene expression patterns. Type 1 ovarian cancer includes endometrioid cancer and clear cell cancer (CCC) (so-called endometriosis-associated ovarian cancer). Endometrioid cancer frequently possesses mutations in phosphatase and Correspondence to: Dr Hiroshi Kobayashi, Department of tensin homolog (PTEN), catenin β1 (CTNNB1), phosphati- Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, dylinositol-4,5-bisphosphate 3-kinase catalytic subunit α Nara 634-8522, Japan E-mail: [email protected] (PIK3CA) and AT-rich interaction domain 1A (ARID1A) (3). PIK3CA and ARID1A are also commonly mutated in CCC Key words: synthetic lethality, ovarian clear cell cancer, PARP and this tumor frequently shows hepatocyte nuclear factor-1β inhibitors, replication stress (HNF-1β) overexpression (3). Although Type 1 cancer often appears as low-stage disease, advanced CCC is a cancer that is highly aggressive with poor patient outcome. By contrast, 392 KAWAHARA et al: SYNTHETIC LETHALITY PARTNERS TO PARP INHIBITORS IN OVARIAN CLEAR CELL CANCER Type 2 ovarian cancer includes high-grade serous ovarian to genomic instability requires various DNA repair genes (9). cancer (HGSC), which is the most common histotype of DDR deficiency results in replication stress, commonly induces epithelial ovarian cancer and is characterized by advanced replication fork slowing or stalling and also activates DNA repair stage at onset. HGSC possesses nearly universal mutation checkpoint proteins [ataxia telangiectasia mutated (ATM), ATM- in and dysfunction of (tumor protein p53) TP53 as well as and Rad3-related (ATR), checkpoint kinase 1 (CHEK1)], which frequent germline and somatic BRCA1/2 (BRCA1/2, DNA prevent further DNA damage (10). DDR regulates cell cycle repair associated) mutations, occurring in at least 30% of arrest, which enables DNA repair to occur. PARP1 plays a key tumors (3). role in numerous cell processes including DNA repair, replication Recent advances for the development of efficient personalized and cell death/survival balance (11). PARP1 is mainly involved therapy may lead to the development of successful strategies in the repair of DNA single-strand breaks. Accumulation of for molecular-targeted medicine (small-molecule inhibitors or DNA double-strand breaks (DSBs) is generally repaired by the antibodies), clinical applications of immunotherapy (PD-1 and two DNA DSB repair pathways: Homologous recombination -L1 antibodies) and identification of synthetic lethal partners (4). (HR) and non-homologous end joining (NHEJ). DNA repair Advances in the treatment of HGSC through use of synthetic defects are frequently encountered in human cancers, whereas lethal approaches have also been made. Notably, inhibitors of DNA repair pathways mediated by PARP1 serve as backups (11). [poly(ADP-ribose) polymerase] (PARP) are considered the Approximately 50% of HGSC incur germline or somatic most active and exciting new personalized target therapy for mutations in genes related to HR [BRCA1/2, BRCA paralogs, the treatment of ovarian cancer, especially relapsed platinum- RAD51 (RAD51 recombinase), checkpoint activation genes and sensitive HGSC (5). However, patients without BRCA1/2 Fanconi's anemia genes] and the rest incur genetic alterations in mutations may also benefit from PARP inhibitors, suggesting a mismatch repair (MMR) genes and other genes in the HR/DNA sensitive non-BRCA1/2-mutation subgroup (6). repair pathway at high frequencies (10). The global genome- The prevalence of CCC in Japan reaches up to 15-25% wide mutational landscape revealed that the majority of HGSC compared to those of North America and Europe with a patients harbor the actionable impact of germline and somatic reported prevalence of 1-12% (7,8). CCC showed a different mutations and DNA repair gene defects. HGSC cells harboring genomic expression map from HGSC, which suggested a new HR deficiencies are exceptionally sensitive to PARP inhibi- target therapy (5). Despite many improvements in targeted tion. PARP inhibitors are an effective treatment strategy when therapy for ovarian cancer, exploration of novel synthetic they are used in BRCA1/2-mutated ovarian cancers, which has lethal targets is required in CCC. Investigators have performed led to a shift in the treatment paradigm of this disease (12,13). computational virtual screenings and further experimental The concept of synthetic lethality interactions can be exploited validations to determine whether two-compound formulations in tumors that harbor germline and somatic mutations causing are susceptible to synthetic lethality and may therefore indi- defective DDR/DNA repair (14). Thus, not only BRCA1/2 muta- cate a therapeutic opportunity. tions, but also other HR deficiencies, have been established as a The aim of the present study was to determine the potential targeted therapy (14). synthetic lethality gene partners for PARP inhibitions in CCC Based on a literature search, we initially identified differen- patients through virtual and biological screenings. tially expressed genes and genomic mutations throughout the ovarian cancer between CCC and HGSC, which were 2. Systematic review of the literature using electronic recapitulated in CCC cell lines in vitro, in xenografts in vivo search in the PubMed/Medline databases and in a comprehensive analysis of clinical data (15-21). We then explored virtual and biological screenings against The study aimed to determine the potential synthetic synthetic lethal gene partners of PARP inhibition in ovarian lethality gene partners for PARP inhibitions in patients with cancer. The majority of samples were derived from patients CCC through virtual and biological screenings as well as with HGSC. Of the candidate genes that were likely to be clinical studies. A PubMed (http://www.ncbi.nlm.nih.gov/ synthetic lethal with PARP inhibitors, we selected genes that pubmed) search of the relevant literature published between were frequently mutated, amplified, or upregulated in CCC.
Load more

Recommended publications
  • The RGG Domain of the Yeast Nucleolin Nsr1 Is Required for The
    bioRxiv preprint doi: https://doi.org/10.1101/802876; this version posted October 13, 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-NC-ND 4.0 International license. 1 The RGG Domain of the Yeast Nucleolin Nsr1 Is Required for the Genome Instability Associated with Co-transcriptionally Formed G4 DNA Shivani Singh1, Alexandra Berroyer1,2, and Nayun Kim1,2,* 1Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA 2MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA *To whom correspondence should be addressed. Tel: 01-713-500-5597; Fax: 01-713-500-5499; Email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/802876; this version posted October 13, 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-NC-ND 4.0 International license. 2 ABSTRACT A significant increase in genome instability is associated with the conformational shift of a guanine-run-containing DNA strand into the four-stranded G4 DNA. Until recently, the mechanism underlying the recombination and genome rearrangements following the formation of G4 DNA in vivo has been difficult to elucidate but has become better clarified by the identification and functional characterization of several key G4 DNA-binding proteins.
    [Show full text]
  • HSF-1 Activates the Ubiquitin Proteasome System to Promote Non-Apoptotic
    HSF-1 Activates the Ubiquitin Proteasome System to Promote Non-Apoptotic Developmental Cell Death in C. elegans Maxime J. Kinet#, Jennifer A. Malin#, Mary C. Abraham, Elyse S. Blum, Melanie Silverman, Yun Lu, and Shai Shaham* Laboratory of Developmental Genetics The Rockefeller University 1230 York Avenue New York, NY 10065 USA #These authors contributed equally to this work *To whom correspondence should be addressed: Tel (212) 327-7126, Fax (212) 327- 7129, email [email protected] Kinet, Malin et al. Abstract Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs have been molecularly characterized, none appear to control developmental cell culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in C. elegans and vertebrate development, and is therefore a compelling candidate process complementing apoptosis. However, the details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal control pathway, and MAPKK signaling control HSF-1, a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin proteasome system, including the E2 ligase LET- 70/UBE2D2 functioning with E3 components CUL-3, RBX-1, BTBD-2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates. 2 Kinet, Malin et al. Introduction Animal development and homeostasis are carefully tuned to balance cell proliferation and death.
    [Show full text]
  • 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.
    [Show full text]
  • Proteomic Identification of the Transcription Factors Ikaros And
    European School of Molecular Medicine (SEMM) University of Milan and University of Naples “Federico II” PhD degree in Systems Medicine (curriculum in Molecular Oncology) Settore disciplinare: BIO/11 Proteomic identification of the transcription factors Ikaros and Aiolos as new Myc interactors on chromatin Chiara Veronica Locarno Matricola: R10755 Center for Genomic Science IIT@SEMM, Milan Supervisor: Bruno Amati, PhD IEO, Milan Added Supervisor: Arianna Sabò, PhD IEO, Milan Academic year 2017-2018 Table of contents List of abbreviations ........................................................................................................... 4 List of figures ....................................................................................................................... 8 List of tables ....................................................................................................................... 11 Abstract .............................................................................................................................. 12 1. INTRODUCTION ......................................................................................................... 13 1.1 Myc ........................................................................................................................................ 13 1.1.1 Myc discovery and structure ........................................................................................... 13 1.1.2. Role of Myc in physiological and pathological conditions ...........................................
    [Show full text]
  • DNA Topoisomerases and Cancer Topoisomerases and TOP Genes in Humans Humans Vs
    DNA Topoisomerases Review DNA Topoisomerases And Cancer Topoisomerases and TOP Genes in Humans Humans vs. Escherichia Coli Topoisomerase differences Comparisons Topoisomerase and genomes Top 1 Top1 and Top2 differences Relaxation of DNA Top1 DNA supercoiling DNA supercoiling In the context of chromatin, where the rotation of DNA is constrained, DNA supercoiling (over- and under-twisting and writhe) is readily generated. TOP1 and TOP1mt remove supercoiling by DNA untwisting, acting as “swivelases”, whereas TOP2a and TOP2b remove writhe, acting as “writhases” at DNA crossovers (see TOP2 section). Here are some basic facts concerning DNA supercoiling that are relevant to topoisomerase activity: • Positive supercoiling (Sc+) tightens the DNA helix whereas negative supercoiling (Sc-) facilitates the opening of the duplex and the generation of single-stranded segments. • Nucleosome formation and disassembly absorbs and releases Sc-, respectively. • Polymerases generate Sc+ ahead and Sc- behind their tracks. • Excess of Sc+ arrests DNA tracking enzymes (helicases and polymerases), suppresses transcription elongation and initiation, and destabilizes nucleosomes. • Sc- facilitates DNA melting during the initiation of replication and transcription, D-loop formation and homologous recombination and nucleosome formation. • Excess of Sc- favors the formation of alternative DNA structures (R-loops, guanine quadruplexes, right-handed DNA (Z-DNA), plectonemic structures), which then absorb Sc- upon their formation and attract regulatory proteins. The
    [Show full text]
  • Zhou Et Al POLQ Inhibitor.Docx
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.23.111658; this version posted May 26, 2020. 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. Polymerase Theta Inhibition Kills Homologous Recombination Deficient Tumors Jia Zhou1, Camille Gelot2, Constantia Pantelidou3, Adam Li1, Hatice Yücel2, Rachel E. Davis4, Anniina Farkkila1, Bose Kochupurakkal1, Aleem Syed5, Geoffrey I. Shapiro3,6, John A. Tainer5, Brian S. J. Blagg4, Raphael Ceccaldi2,7* and Alan D. D’Andrea1,6,7* 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. 2Inserm U830, PSL Research University, Institut Curie, 75005, Paris, France. 3Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 4Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA. 5Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 6Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, USA. 7Co-senior authors. * Co-corresponding authors. * Corresponding authors: Alan D. D’Andrea, M.D. Director, Susan F. Smith Center for Women’s Cancers (SFSCWC) Director, Center for DNA Damage and Repair Dana-Farber Cancer Institute The Fuller-American Cancer Society Professor Harvard Medical School Phone: 617-632-2080 Email: [email protected] Raphael Ceccaldi Institut Curie, 75005, Paris, France Phone: +33 (0)1 56 24 69 49 Email: [email protected] Key Words: Novobiocin, Polymerase theta (POLθ), Homologous Recombination, PARP inhibitor resistance.
    [Show full text]
  • 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.
    [Show full text]
  • Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers
    Published OnlineFirst June 12, 2020; DOI: 10.1158/2159-8290.CD-20-0163 RESEARCH ARTICLE Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers Timothy A. Yap1,2, Rebecca Kristeleit3, Vasiliki Michalarea1, Stephen J. Pettitt4,5, Joline S.J. Lim1, Suzanne Carreira2, Desamparados Roda1,2, Rowan Miller3, Ruth Riisnaes2, Susana Miranda2, Ines Figueiredo2, Daniel Nava Rodrigues2, Sarah Ward1,2, Ruth Matthews1,2, Mona Parmar1,2, Alison Turner1,2, Nina Tunariu1, Neha Chopra1,4, Heidrun Gevensleben2, Nicholas C. Turner1,4, Ruth Ruddle2, Florence I. Raynaud2, Shaun Decordova2, Karen E. Swales2, Laura Finneran2, Emma Hall2, Paul Rugman6, Justin P.O. Lindemann6, Andrew Foxley6, Christopher J. Lord4,5, Udai Banerji1,2, Ruth Plummer7, Bristi Basu8, Juanita S. Lopez1,2, Yvette Drew7, and Johann S. de Bono1,2 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst June 12, 2020; DOI: 10.1158/2159-8290.CD-20-0163 ABSTRACT Preclinical studies have demonstrated synergy between PARP and PI3K/AKT path- way inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient andBRCA1/2 -proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibi- tor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off.
    [Show full text]
  • NBN Gene Analysis and It's Impact on Breast Cancer
    Journal of Medical Systems (2019) 43: 270 https://doi.org/10.1007/s10916-019-1328-z IMAGE & SIGNAL PROCESSING NBN Gene Analysis and it’s Impact on Breast Cancer P. Nithya1 & A. ChandraSekar1 Received: 8 March 2019 /Accepted: 7 May 2019 /Published online: 5 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Single Nucleotide Polymorphism (SNP) researches have become essential in finding out the congenital relationship of structural deviations with quantitative traits, heritable diseases and physical responsiveness to different medicines. NBN is a protein coding gene (Breast Cancer); Nibrin is used to fix and rebuild the body from damages caused because of strand breaks (both singular and double) associated with protein nibrin. NBN gene was retrieved from dbSNP/NCBI database and investigated using computational SNP analysis tools. The encrypted region in SNPs (exonal SNPs) were analyzed using software tools, SIFT, Provean, Polyphen, INPS, SNAP and Phd-SNP. The 3’ends of SNPs in un-translated region were also investigated to determine the impact of binding. The association of NBN gene polymorphism leads to several diseases was studied. Four SNPs were predicted to be highly damaged in coding regions which are responsible for the diseases such as, Aplastic Anemia, Nijmegan breakage syndrome, Microsephaly normal intelligence, immune deficiency and hereditary cancer predisposing syndrome (clivar). The present study will be helpful in finding the suitable drugs in future for various diseases especially for breast cancer. Keywords NBN . Single nucleotide polymorphism . Double strand breaks . nsSNP . Associated diseases Introduction NBN has a more complex structure due to its interaction with large proteins formed from the ATM gene which is NBN (Nibrin) is a protein coding gene, it is also known as highly essential in identifying damaged strands of DNA NBS1, Cell cycle regulatory Protein P95, is situated on and facilitating their repair [1].
    [Show full text]
  • Human DNA Topoisomerase I Is Encoded by a Single-Copy Gene That Maps to Chromosome Region 20Q12-13.2
    Proc. Nati. Acad. Sci. USA Vol. 85, pp. 8910-8913, December 1988 Biochemistry Human DNA topoisomerase I is encoded by a single-copy gene that maps to chromosome region 20q12-13.2 (human TOP) gene/molecular cloning/in situ hybridization/mouse-human hybrids) CHUNG-CHING JUAN*, JAULANG HWANG*, ANGELA A. LIu*, JACQUELINE WHANG-PENGt, TURID KNUTSENt, KAY HUEBNERt, CARLO M. CROCEO, Hui ZHANG§, JAMES C. WANG$, AND LEROY F. Liu§ *Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan 11529, Republic of China; tMedicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; tWistar Institute, 36th Street at Spruce, Philadelphia, PA 19104; IDepartment of Biochemistry and Molecular Biology, Harvard University, Cambridge, MA 02138; §Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 Contributed by James C. Wang, August 24, 1988 ABSTRACT cDNA clones of the human TOP) gene encod- ofthe enzyme by DNA topoisomerase II (EC 5.99.1.3), a type ing DNA topoisomerase I (EC 5.99.1.2) have been obtained by II topoisomerase (15). immunochemical screening of phage A libraries expressing Recent studies identify the DNA topoisomerases as the human cDNA segments, using rabbit antibodies raised against targets of a number of anticancer drugs (16-20). Whereas the purified HeLa DNA topoisomerase I. Hybridization patterns majority of these therapeutics act on DNA topoisomerase II, between the cloned cDNA sequences and human cellular DNA one, the plant alkaloid camptothecin, acts on DNA topo- and cytoplasmic mRNAs indicate that human TOP) is a isomerase I (21-25). The biological and clinical importance of single-copy gene.
    [Show full text]
  • Investigation of the Underlying Hub Genes and Molexular Pathogensis in Gastric Cancer by Integrated Bioinformatic Analyses
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Investigation of the underlying hub genes and molexular pathogensis in gastric cancer by integrated bioinformatic analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The high mortality rate of gastric cancer (GC) is in part due to the absence of initial disclosure of its biomarkers. The recognition of important genes associated in GC is therefore recommended to advance clinical prognosis, diagnosis and and treatment outcomes. The current investigation used the microarray dataset GSE113255 RNA seq data from the Gene Expression Omnibus database to diagnose differentially expressed genes (DEGs). Pathway and gene ontology enrichment analyses were performed, and a proteinprotein interaction network, modules, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. Finally, validation of hub genes was performed. The 1008 DEGs identified consisted of 505 up regulated genes and 503 down regulated genes.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]