Functional Impacts of the Ubiquitin–Proteasome System on DNA
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Variant Requirements for DNA Repair Proteins in Cancer Cell Lines That Use
Variant requirements for DNA repair proteins in cancer cell lines that use alternative lengthening of telomere mechanisms of elongation DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Alaina Rae Martinez Biomedical Sciences Graduate Program The Ohio State University 2016 Dissertation Committee: Dr. Jeffrey D. Parvin, Advisor Dr. Joanna Groden Dr. Amanda E. Toland Dr. Kay F. Huebner Copyright by Alaina Rae Martinez 2016 Abstract The human genome relies on DNA repair proteins and the telomere to maintain genome stability. Genome instability is recognized as a hallmark of cancer, as is limitless replicative capacity. Cancer cells require telomere maintenance to enable this uncontrolled growth. Most often telomerase is activated, although a subset of human cancers depend on recombination-based mechanisms known as Alternative Lengthening of Telomeres (ALT). ALT depends invariably on recombination and its associated DNA repair proteins to extend telomeres. This study tested the hypothesis that the requirement for those requisite recombination proteins include other types of DNA repair proteins. These functions were tested in ALT cell lines using C-circle abundance as a marker of ALT. The requirement for homologous recombination proteins and other DNA repair proteins varied between ALT cell lines compared. Several proteins essential for homologous recombination were dispensable for C-circle production in some ALT cell lines, while proteins grouped into excision DNA repair processes were required for C- circle production. The MSH2 mismatch repair protein was required for telomere recombination by intertelomeric exchange. In sum, our study suggests that ALT proceeds by multiple mechanisms that differ between human cancer cell lines and that some of these depend on DNA repair proteins not associated with homologous recombination pathways. -
Structure and Function of the Human Recq DNA Helicases
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2005 Structure and function of the human RecQ DNA helicases Garcia, P L Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-34420 Dissertation Published Version Originally published at: Garcia, P L. Structure and function of the human RecQ DNA helicases. 2005, University of Zurich, Faculty of Science. Structure and Function of the Human RecQ DNA Helicases Dissertation zur Erlangung der naturwissenschaftlichen Doktorw¨urde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultat¨ der Universitat¨ Z ¨urich von Patrick L. Garcia aus Unterseen BE Promotionskomitee Prof. Dr. Josef Jiricny (Vorsitz) Prof. Dr. Ulrich H ¨ubscher Dr. Pavel Janscak (Leitung der Dissertation) Z ¨urich, 2005 For my parents ii Summary The RecQ DNA helicases are highly conserved from bacteria to man and are required for the maintenance of genomic stability. All unicellular organisms contain a single RecQ helicase, whereas the number of RecQ homologues in higher organisms can vary. Mu- tations in the genes encoding three of the five human members of the RecQ family give rise to autosomal recessive disorders called Bloom syndrome, Werner syndrome and Rothmund-Thomson syndrome. These diseases manifest commonly with genomic in- stability and a high predisposition to cancer. However, the genetic alterations vary as well as the types of tumours in these syndromes. Furthermore, distinct clinical features are observed, like short stature and immunodeficiency in Bloom syndrome patients or premature ageing in Werner Syndrome patients. Also, the biochemical features of the human RecQ-like DNA helicases are diverse, pointing to different roles in the mainte- nance of genomic stability. -
DDB1 Targets Chk1 to the Cul4 E3 Ligase Complex in Normal Cycling Cells and in Cells Experiencing Replication Stress
Published OnlineFirst March 10, 2009; DOI: 10.1158/0008-5472.CAN-08-3382 Research Article DDB1 Targets Chk1 to the Cul4 E3 Ligase Complex in Normal Cycling Cells and in Cells Experiencing Replication Stress Van Leung-Pineda,1 Jiwon Huh,1 and Helen Piwnica-Worms1,2,3 Departments of 1Cell Biology and Physiology and 2Internal Medicine and 3Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri Abstract protein FANCE (8, 10–12). Chk1 carries out its functions both in the The Chk1 protein kinase preserves genome integrity in normal nucleus and at the centrosome (13). Drugs that block Chk1 kinase proliferating cells and in cells experiencing replicative and activity or enhance its proteolysis by interfering with binding to genotoxic stress. Chk1 is currently being targeted in antican- heat shock protein 90 (HSP90) are currently being tested as cer regimens. Here, we identify damaged DNA-binding protein anticancer agents (14–17). 1 (DDB1) as a novel Chk1-interacting protein. DDB1 is part of Chk1 is regulated by reversible phosphorylation and by an E3 ligase complex that includes the cullin proteins Cul4A ubiquitin-mediated proteolysis. Under periods of replicative stress, and Cul4B. We report that Cul4A/DDB1 negatively regulates the ATRIP/ATR module binds to single-stranded DNA and, Chk1 stability in vivo. Chk1 associates with Cul4A/DDB1 together with Rad17 and the 9-1-1 complex, activates Chk1 in a Claspin-dependent manner (18–22). ATR directly phosphorylates during an unperturbed cell division cycle and both Chk1 317 345 phosphorylation and replication stress enhanced these inter- Chk1 on two COOH-terminal residues: Ser (S317) and Ser actions. -
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CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders Michael F. Walsh1, Vivian Y. Chang2, Wendy K. Kohlmann3, Hamish S. Scott4, Christopher Cunniff5, Franck Bourdeaut6, Jan J. Molenaar7, Christopher C. Porter8, John T. Sandlund9, Sharon E. Plon10, Lisa L. Wang10, and Sharon A. Savage11 Abstract DNA repair syndromes are heterogeneous disorders caused by around the world to discuss and develop cancer surveillance pathogenic variants in genes encoding proteins key in DNA guidelines for children with cancer-prone disorders. Herein, replication and/or the cellular response to DNA damage. The we focus on the more common of the rare DNA repair dis- majority of these syndromes are inherited in an autosomal- orders: ataxia telangiectasia, Bloom syndrome, Fanconi ane- recessive manner, but autosomal-dominant and X-linked reces- mia, dyskeratosis congenita, Nijmegen breakage syndrome, sive disorders also exist. The clinical features of patients with DNA Rothmund–Thomson syndrome, and Xeroderma pigmento- repair syndromes are highly varied and dependent on the under- sum. Dedicated syndrome registries and a combination of lying genetic cause. Notably, all patients have elevated risks of basic science and clinical research have led to important in- syndrome-associated cancers, and many of these cancers present sights into the underlying biology of these disorders. Given the in childhood. Although it is clear that the risk of cancer is rarity of these disorders, it is recommended that centralized increased, there are limited data defining the true incidence of centers of excellence be involved directly or through consulta- cancer and almost no evidence-based approaches to cancer tion in caring for patients with heritable DNA repair syn- surveillance in patients with DNA repair disorders. -
Identification of Novel Pathogenic MSH2 Mutation and New DNA Repair Genes Variants: Investigation of a Tunisian Lynch Syndrome F
Jaballah‑Gabteni et al. J Transl Med (2019) 17:212 https://doi.org/10.1186/s12967‑019‑1961‑9 Journal of Translational Medicine RESEARCH Open Access Identifcation of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins Amira Jaballah‑Gabteni1,3* , Haifa Tounsi1,3, Maria Kabbage1,3, Yosr Hamdi3, Sahar Elouej3,4, Ines Ben Ayed1,3, Mouna Medhioub2, Moufda Mahmoudi2, Hamza Dallali3, Hamza Yaiche1,3, Nadia Ben Jemii1,3, Affa Maaloul1, Najla Mezghani1,3, Sonia Abdelhak3, Lamine Hamzaoui2, Mousaddak Azzouz2 and Samir Boubaker1,3 Abstract Background: Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome, characterized by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. Despite several genetic variations that have been identifed in various populations, the penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether, besides pathogenic mutations, environment and low penetrance genetic risk factors may result in phenotype modifcation in a Tunisian LS family. Patients and methods: A Tunisian family with strong colorectal cancer (CRC) history that fulfll the Amsterdam I criteria for the diagnosis of Lynch syndrome was proposed for oncogenetic counseling. The index case was a man, diagnosed at the age of 33 years with CRC. He has a monozygotic twin diagnosed at the age of 35 years with crohn disease. Forty‑seven years‑old was the onset age of his paternal uncle withCRC. An immunohistochemical (IHC) labe‑ ling for the four proteins (MLH1, MSH2, MSH6 and PMS2) of the MisMatchRepair (MMR) system was performed for the index case. -
Deubiquitinases in Cancer: New Functions and Therapeutic Options
Oncogene (2012) 31, 2373–2388 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc REVIEW Deubiquitinases in cancer: new functions and therapeutic options JM Fraile1, V Quesada1, D Rodrı´guez, JMP Freije and C Lo´pez-Otı´n Departamento de Bioquı´mica y Biologı´a Molecular, Facultad de Medicina, Instituto Universitario de Oncologı´a, Universidad de Oviedo, Oviedo, Spain Deubiquitinases (DUBs) have fundamental roles in the Hunter, 2010). Consistent with the functional relevance ubiquitin system through their ability to specifically of proteases in these processes, alterations in their deconjugate ubiquitin from targeted proteins. The human structure or in the mechanisms controlling their genome encodes at least 98 DUBs, which can be grouped spatiotemporal expression patterns and activities cause into 6 families, reflecting the need for specificity in diverse pathologies such as arthritis, neurodegenerative their function. The activity of these enzymes affects the alterations, cardiovascular diseases and cancer. Accord- turnover rate, activation, recycling and localization ingly, many proteases are an important focus of of multiple proteins, which in turn is essential for attention for the pharmaceutical industry either as drug cell homeostasis, protein stability and a wide range of targets or as diagnostic and prognostic biomarkers signaling pathways. Consistent with this, altered DUB (Turk, 2006; Drag and Salvesen, 2010). function has been related to several diseases, including The recent availability of the genome sequence cancer. Thus, multiple DUBs have been classified as of different organisms has facilitated the identification oncogenes or tumor suppressors because of their regula- of their entire protease repertoire, which has been tory functions on the activity of other proteins involved in defined as degradome (Lopez-Otin and Overall, 2002). -
Case-Control Analysis Identifies Shared Properties of Rare Germline Variation in Cancer Predisposing Genes
Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes Mykyta Artomov1,2, Vijai Joseph3, Grace Tiao1,2, Tinu Thomas3, Kasmintan Schrader3, Robert J. Klein3, Adam Kiezun2, Namrata Gupta2, Lauren MarGolin2, Alexander J. StratiGos4, Ivana Kim5, Kristen Shannon6, Leif W. Ellisen6,7, Daniel Haber6,7,8, Gad Getz2, Hensin Tsao9,10, Steven M. Lipkin11, David Altshuler2, Kenneth Offit*3,12 and Mark J. Daly*1,2 1Analytic and Translational Genetics Unit, MGH, Boston, MA, USA 2Broad Institute, CambridGe, MA, USA 3 Clinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan KetterinG Cancer Center, New York, NY, USA 41st Department of DermatoloGy-VenereoloGy, National and Kapodistrian University of Athens School of Medicine, Andreas SyGros Hospital, Athens, Greece 5 Retina Service, Massachusetts Eye and Ear Infirmary, Boston, MA, USA 6 Massachusetts General Hospital Cancer Center, Boston, MA, USA 7 Harvard Medical School, Boston, MA, USA 8 Howard HuGhes Medical Institute, Chevy Chase, Maryland 20815, USA 9 Department of DermatoloGy, Wellman Center for Photomedicine, MGH, Boston, MA, USA 10 Melanoma Genetics ProGram, MGH Cancer Center, MGH, Boston, MA, USA 11 Department of Medicine, ProGram in Mendelian Genetics, Weill-Cornell Medicine, New York, NY, USA 12 Cancer BioloGy and Genetics ProGram, Sloan KetterinG Institute, New York, NY, USA Correspondence: Mark J. Daly, 185 CambridGe St, CPZN-6823A, Boston, MA, 02114, USA; [email protected]; phone: (617)-726-5936 Kenneth Offit, Memorial Sloan KetterinG Cancer Center, 1275 York Avenue, New York, NY, 10065; [email protected]; phone: (212)-639-2000 Authors declare no conflict of interests SUPPLEMENTARY INFORMATION Patient cohorts ......................................................................................................................................... -
Dissertation Submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University O
Dissertation submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany For the degree of Doctor of Natural Sciences Presented by M.Phil - Rashda Abbasi Born in Karachi, Pakistan Oral-examination:…………………………… I II Nucleotide excision repair pathway modulating both cancer risk and therapy Referees: Prof. Dr. Thomas Efferth PD Dr. Rajiv Kumar III IV Division: Epigenomics and Cancer Risk Factors Head of the division: Prof. Dr. Christoph Plass Deutsches Krebsforschungszentrum (DKFZ) in the Helmholtz Association Heidelberg V VI DECLARATION This thesis is a presentation of my original research work and that it has not been submitted anywhere for any award. Wherever contributions of others are involved, every effort is made to indicate this clearly, with due reference to the literature. Heidelberg, 1st December, 2009 Rashda Abbasi VII VIII In The Name Of Allah, The Most Beneficent, The Most Merciful IX X Summary Summary Nucleotide excision repair (NER) plays a key role in repairing a wide variety of DNA damage including bulky DNA adducts caused by ultraviolet radiation and exposure to harmful substances like tobacco smoke and alcohol. Genetic variations and somatic mutations in NER genes might affect cancer risk and therapy. However, both these aspects are not well understood. The first part of the thesis deals with the role of NER in modulation of laryngeal cancer risk. The major risk factors for laryngeal cancer are smoking and high alcohol consumption. Polymorphisms in NER genes might therefore affect laryngeal cancer susceptibility. In a population-based case-control study including 248 cases and 647 controls, the association of laryngeal cancer with 11 single nucleotide polymorphisms (SNPs) in 7 NER genes (XPC, ERCC1, ERCC2, ERCC4, ERCC5, ERCC6 and RAD23B) was analyzed with respect to smoking and alcohol exposure. -
The Differential Expression of Core Genes in Nucleotide Excision Repair Pathway Indicates Colorectal Carcinogenesis and Prognosis
Hindawi BioMed Research International Volume 2018, Article ID 9651320, 10 pages https://doi.org/10.1155/2018/9651320 Research Article The Differential Expression of Core Genes in Nucleotide Excision Repair Pathway Indicates Colorectal Carcinogenesis and Prognosis Jingwei Liu, Hao Li, Liping Sun, Xue Feng, Zhenning Wang , Yuan Yuan , and Chengzhong Xing Tumor Etiology and Screening Department, Cancer Institute and General Surgery, Te First Hospital of China Medical University and Key Laboratory of Cancer Etiology and Prevention, Liaoning Provincial Education Department, China Medical University, Shenyang 110001, China Correspondence should be addressed to Yuan Yuan; [email protected] and Chengzhong Xing; [email protected] Received 19 October 2017; Revised 12 December 2017; Accepted 14 December 2017; Published 15 January 2018 Academic Editor: Paul W. Doetsch Copyright © 2018 Jingwei Liu et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Nucleotide excision repair (NER) plays a critical role in maintaining genome integrity. Tis study aimed to investigate theexpressionofNERgenesandtheirassociationswithcolorectalcancer(CRC)development.Method. Expressions of NER genes in CRC and normal tissues were analysed by ONCOMINE. Te Cancer Genome Atlas (TCGA) data were downloaded to explore relationship of NER expression with clinicopathological parameters and survival of CRC. Results. ERCC1, ERCC2, ERCC5, and DDB2 were upregulated while ERCC4 was downregulated in CRC. For colon cancer, high ERCC3 expression was related to better T stage; ERCC5 expression indicated deeper T stage and distant metastasis; DDB2 expression suggested earlier TNM stage. For rectal cancer, ERCC2 expression correlated with favourable T stage; XPA expression predicted worse TNM stage. -
(UV-DDB) Dimerization and Its Roles in Chromatinized DNA Repair
Damaged DNA induced UV-damaged DNA-binding protein (UV-DDB) dimerization and its roles in chromatinized DNA repair Joanne I. Yeha,b,1, Arthur S. Levinec,d, Shoucheng Dua, Unmesh Chintea, Harshad Ghodkee, Hong Wangd,e, Haibin Shia, Ching L. Hsiehc,d, James F. Conwaya, Bennett Van Houtend,e, and Vesna Rapić-Otrinc,d aDepartments of Structural Biology, bBioengineering, cMicrobiology and Molecular Genetics, ePharmacology and Chemical Biology, and dUniversity of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260 AUTHOR SUMMARY Exposure to UV radiation (DDB1-CUL4A DDB2) with can damage DNA that if chromatin modification and left unrepaired can cause the subsequent steps in the mutations leading to skin repair pathway. aging and skin cancer. In Here we report the crystal humans, the nucleotide structure of the full-length excision repair (NER) * human DDB2 bound to proteins function to damaged DNA in a complex recognize and repair with human DDB1 (Fig. P1). UV-damaged DNA. Defects While a large portion of the in DNA repair caused by N-terminal region of the mutations of these repair zebrafish DDB2 in the proteins have been linked earlier structure could not to several genetic diseases, be modeled, we have characterized by cancer resolved the 3D structure of predisposition (xeroderma the N-terminal domain of pigmentosum, XP) or DDB2. Our structure reveals premature aging (Cockayne secondary interactions syndrome), illustrating the between the N-terminal Fig. P1. Composite model of a dimeric DDB1-CUL4ADDB2 ubiquitin functional significance of DDB2 domain of DDB2 and a ligase-nucleosome complex. A model of a dimeric DDB1-CUL4A in a neighboring repair proteins to genomic complex with a nucleosome core particle, generated according to the relative integrity. -
Evidence for Premature Aging Due to Oxidative Stress in Ipscs from Cockayne Syndrome
Human Molecular Genetics, 2012, Vol. 21, No. 17 3825–3834 doi:10.1093/hmg/dds211 Advance Access published on June 1, 2012 Evidence for premature aging due to oxidative stress in iPSCs from Cockayne syndrome Luciana Nogueira de Sousa Andrade1,2,3, Jason L. Nathanson2, Gene W. Yeo2, Carlos Frederico Martins Menck3 and Alysson Renato Muotri1,2,∗ 1School of Medicine, Department of Pediatrics/Rady Children’s Hospital San Diego and 2Department of Cellular & Molecular Medicine, University of California San Diego, Stem Cell Program, 2880 Torrey Pines Scenic Road - Sanford Consortium, La Jolla, CA 92093, MC 0695, USA and 3Department of Microbiology, DNA Repair Laboratory, Downloaded from Biomedical Institute, University of Sa˜o Paulo, 1374 Av. Prof. Lineu Prestes, Sa˜o Paulo, SP 05508-000, Brazil Received March 28, 2012; Revised May 18, 2012; Accepted May 28, 2012 Cockayne syndrome (CS) is a human premature aging disorder associated with neurological and develop- http://hmg.oxfordjournals.org/ mental abnormalities, caused by mutations mainly in the CS group B gene (ERCC6). At the molecular level, CS is characterized by a deficiency in the transcription-couple DNA repair pathway. To understand the role of this molecular pathway in a pluripotent cell and the impact of CSB mutation during human cellular development, we generated induced pluripotent stem cells (iPSCs) from CSB skin fibroblasts (CSB-iPSC). Here, we showed that the lack of functional CSB does not represent a barrier to genetic reprogramming. However, iPSCs derived from CSB patient’s fibroblasts exhibited elevated cell death rate and higher reactive oxygen species (ROS) production. Moreover, these cellular phenotypes were accompanied by an up-regulation of TXNIP and TP53 transcriptional expression. -
PSMD14 Is Over-Expressed in Human Endometrial Cancer
Over-expression of proteasome 26S subunit, non-ATPase 14 in human endometrial cancer. Shahan Mamoor, MS1 [email protected] East Islip, NY USA Gynecologic cancers including cancers of the endometrium are a clinical problem1-4. We mined published microarray data5,6 to discover genes associated with endometrial cancers by comparing transcriptomes of the normal and hyperplastic endometrium to endometrial tumors from humans. We identified proteasome 26S subunit, non-ATPase 14, encoded by PSMD14, as among the most differentially expressed genes, transcriptome-wide, in cancers of the endometrium. PSMD14 was expressed at significantly higher levels in endometrial tumor tissues as compared to the endometrium. Importantly, in human endometrial cancer, primary tumor expression of PSMD14 was correlated with overall survival in white patients with low mutational burden. PSMD14 may be a molecule of interest in understanding the etiology or progression of human endometrial cancer. Keywords: endometrial cancer, gynecologic cancers, endometrium, PSMD14, proteasome 26S subunit, non-ATPase 14, systems biology of endometrial cancer, targeted therapeutics in endometrial cancer. 1 Endometrial cancer is the most common gynecologic cancer in the developed world1. Over the last three decades, the incidence of endometrial cancer has increased 21%4 and the death rate has increased 100%3. We harnessed the power of independently published microarray datasets5,6 to determine in an unbiased fashion and at the systems-level genes most differentially expressed in endometrial tumors. We report here the differential and increased expression of the proteasome 26S subunit, non-ATPase 14 (PSMD14) in human endometrial cancer. Methods We utilized datasets GSE636785 and GSE1061916 for this global differential gene expression analysis of human endometrial cancer in conjunction with GEO2R.