Rethinking Origin Licensing
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Functional Roles of Bromodomain Proteins in Cancer
cancers Review Functional Roles of Bromodomain Proteins in Cancer Samuel P. Boyson 1,2, Cong Gao 3, Kathleen Quinn 2,3, Joseph Boyd 3, Hana Paculova 3 , Seth Frietze 3,4,* and Karen C. Glass 1,2,4,* 1 Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA; [email protected] 2 Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA; [email protected] 3 Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; [email protected] (C.G.); [email protected] (J.B.); [email protected] (H.P.) 4 University of Vermont Cancer Center, Burlington, VT 05405, USA * Correspondence: [email protected] (S.F.); [email protected] (K.C.G.) Simple Summary: This review provides an in depth analysis of the role of bromodomain-containing proteins in cancer development. As readers of acetylated lysine on nucleosomal histones, bromod- omain proteins are poised to activate gene expression, and often promote cancer progression. We examined changes in gene expression patterns that are observed in bromodomain-containing proteins and associated with specific cancer types. We also mapped the protein–protein interaction network for the human bromodomain-containing proteins, discuss the cellular roles of these epigenetic regu- lators as part of nine different functional groups, and identify bromodomain-specific mechanisms in cancer development. Lastly, we summarize emerging strategies to target bromodomain proteins in cancer therapy, including those that may be essential for overcoming resistance. Overall, this review provides a timely discussion of the different mechanisms of bromodomain-containing pro- Citation: Boyson, S.P.; Gao, C.; teins in cancer, and an updated assessment of their utility as a therapeutic target for a variety of Quinn, K.; Boyd, J.; Paculova, H.; cancer subtypes. -
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. -
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. -
The Architecture of a Eukaryotic Replisome
The Architecture of a Eukaryotic Replisome Jingchuan Sun1,2, Yi Shi3, Roxana E. Georgescu3,4, Zuanning Yuan1,2, Brian T. Chait3, Huilin Li*1,2, Michael E. O’Donnell*3,4 1 Biosciences Department, Brookhaven National Laboratory, Upton, New York, USA 2 Department of Biochemistry & Cell Biology, Stony Brook University, Stony Brook, New York, USA. 3 The Rockefeller University, 1230 York Avenue, New York, New York, USA. 4 Howard Hughes Medical Institute *Correspondence and requests for materials should be addressed to M.O.D. ([email protected]) or H.L. ([email protected]) ABSTRACT At the eukaryotic DNA replication fork, it is widely believed that the Cdc45-Mcm2-7-GINS (CMG) helicase leads the way in front to unwind DNA, and that DNA polymerases (Pol) trail behind the helicase. Here we use single particle electron microscopy to directly image a replisome. Contrary to expectations, the leading strand Pol ε is positioned ahead of CMG helicase, while Ctf4 and the lagging strand Pol α-primase (Pol α) are behind the helicase. This unexpected architecture indicates that the leading strand DNA travels a long distance before reaching Pol ε, it first threads through the Mcm2-7 ring, then makes a U-turn at the bottom to reach Pol ε at the top of CMG. Our work reveals an unexpected configuration of the eukaryotic replisome, suggests possible reasons for this architecture, and provides a basis for further structural and biochemical replisome studies. INTRODUCTION DNA is replicated by a multi-protein machinery referred to as a replisome 1,2. Replisomes contain a helicase to unwind DNA, DNA polymerases that synthesize the leading and lagging strands, and a primase that makes short primed sites to initiate DNA synthesis on both strands. -
Orpl, a Member of the Cdcl8/Cdc6 Family of S-Phase Regulators, Is Homologous to a Component of the Origin Recognition Complex M
Proc. Natl. Acad. Sci. USA Vol. 92, pp. 12475-12479, December 1995 Genetics Orpl, a member of the Cdcl8/Cdc6 family of S-phase regulators, is homologous to a component of the origin recognition complex M. MuzI-FALCONI AND THOMAS J. KELLY Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Contributed by Thomas J. Kelly, September 11, 1995 ABSTRACT cdc18+ of Schizosaccharomyces pombe is a is the cdcJ8+ gene (1, 15). Expression of cdcJ8+ from a periodically expressed gene that is required for entry into S heterologous promoter is sufficient to rescue the lethality of a phase and for the coordination of S phase with mitosis. cdc18+ conditional temperature-sensitive (ts) cdc O's mutant. The is related to the Saccharomyces cerevisiae gene CDC6, which has cdcJ8+ gene product, a 65-kDa protein, is essential for the also been implicated in the control of DNA replication. We GI/S transition. Moreover, p65cdclS is a highly labile protein have identified a new Sch. pombe gene, orpl1, that encodes an whose expression is confined to a narrow window at the G,/S 80-kDa protein with amino acid sequence motifs conserved in boundary (unpublished data). These properties are consistent the Cdc18 and Cdc6 proteins. Genetic analysis indicates that with the hypothesis that Cdc18 may play an important role in orpi + is essential for viability. Germinating spores lacking the regulating the initiation of DNA replication at S phase. The orpl + gene are capable of undergoing one or more rounds of Cdc18 protein is homologous to the budding yeast Cdc6 DNA replication but fail to progress further, arresting as long protein, which may have a similar function (16). -
Derepression of Htert Gene Expression Promotes Escape from Oncogene-Induced Cellular Senescence
Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence Priyanka L. Patela, Anitha Surama, Neena Miranib, Oliver Bischofc,d, and Utz Herbiga,e,1 aNew Jersey Medical School-Cancer Center, Rutgers Biomedical and Health Sciences, Newark, NJ 07103; bDepartment of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103; cNuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, Institut Pasteur, 75015 Paris, France; dINSERM U993, F-75015 Paris, France; and eDepartment of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103 Edited by Victoria Lundblad, Salk Institute for Biological Studies, La Jolla, CA, and approved June 27, 2016 (received for review February 11, 2016) Oncogene-induced senescence (OIS) is a critical tumor-suppressing that occur primarily at fragile sites. The ensuing DNA damage mechanism that restrains cancer progression at premalignant stages, response (DDR) triggers OIS, thereby arresting cells within a few in part by causing telomere dysfunction. Currently it is unknown cell-division cycles after oncogene expression (8, 9). Although most whether this proliferative arrest presents a stable and therefore DSBs in arrested cells are eventually resolved by cellular DSB irreversible barrier to cancer progression. Here we demonstrate that repair processes, some persist and consequently convert the other- cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, wise transient DDR into a more permanent growth arrest. We and after a prolonged period in the senescence arrested state. Cells that others have demonstrated that the persistent DDR is primarily had escaped senescence displayed high oncogene expression levels, telomeric, triggered by irreparable telomeric DSBs (1, 10, 11). -
Supplementary Table S1. Correlation Between the Mutant P53-Interacting Partners and PTTG3P, PTTG1 and PTTG2, Based on Data from Starbase V3.0 Database
Supplementary Table S1. Correlation between the mutant p53-interacting partners and PTTG3P, PTTG1 and PTTG2, based on data from StarBase v3.0 database. PTTG3P PTTG1 PTTG2 Gene ID Coefficient-R p-value Coefficient-R p-value Coefficient-R p-value NF-YA ENSG00000001167 −0.077 8.59e-2 −0.210 2.09e-6 −0.122 6.23e-3 NF-YB ENSG00000120837 0.176 7.12e-5 0.227 2.82e-7 0.094 3.59e-2 NF-YC ENSG00000066136 0.124 5.45e-3 0.124 5.40e-3 0.051 2.51e-1 Sp1 ENSG00000185591 −0.014 7.50e-1 −0.201 5.82e-6 −0.072 1.07e-1 Ets-1 ENSG00000134954 −0.096 3.14e-2 −0.257 4.83e-9 0.034 4.46e-1 VDR ENSG00000111424 −0.091 4.10e-2 −0.216 1.03e-6 0.014 7.48e-1 SREBP-2 ENSG00000198911 −0.064 1.53e-1 −0.147 9.27e-4 −0.073 1.01e-1 TopBP1 ENSG00000163781 0.067 1.36e-1 0.051 2.57e-1 −0.020 6.57e-1 Pin1 ENSG00000127445 0.250 1.40e-8 0.571 9.56e-45 0.187 2.52e-5 MRE11 ENSG00000020922 0.063 1.56e-1 −0.007 8.81e-1 −0.024 5.93e-1 PML ENSG00000140464 0.072 1.05e-1 0.217 9.36e-7 0.166 1.85e-4 p63 ENSG00000073282 −0.120 7.04e-3 −0.283 1.08e-10 −0.198 7.71e-6 p73 ENSG00000078900 0.104 2.03e-2 0.258 4.67e-9 0.097 3.02e-2 Supplementary Table S2. -
Gene Expression Profiling Analysis Contributes to Understanding the Association Between Non-Syndromic Cleft Lip and Palate, and Cancer
2110 MOLECULAR MEDICINE REPORTS 13: 2110-2116, 2016 Gene expression profiling analysis contributes to understanding the association between non-syndromic cleft lip and palate, and cancer HONGYI WANG, TAO QIU, JIE SHI, JIULONG LIANG, YANG WANG, LIANGLIANG QUAN, YU ZHANG, QIAN ZHANG and KAI TAO Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China Received March 10, 2015; Accepted December 18, 2015 DOI: 10.3892/mmr.2016.4802 Abstract. The present study aimed to investigate the for NSCL/P were implicated predominantly in the TGF-β molecular mechanisms underlying non-syndromic cleft lip, signaling pathway, the cell cycle and in viral carcinogenesis. with or without cleft palate (NSCL/P), and the association The TP53, CDK1, SMAD3, PIK3R1 and CASP3 genes were between this disease and cancer. The GSE42589 data set found to be associated, not only with NSCL/P, but also with was downloaded from the Gene Expression Omnibus data- cancer. These results may contribute to a better understanding base, and contained seven dental pulp stem cell samples of the molecular mechanisms of NSCL/P. from children with NSCL/P in the exfoliation period, and six controls. Differentially expressed genes (DEGs) were Introduction screened using the RankProd method, and their potential functions were revealed by pathway enrichment analysis and Non-syndromic cleft lip, with or without cleft palate (NSCL/P) construction of a pathway interaction network. Subsequently, is one of the most common types of congenital defect and cancer genes were obtained from six cancer databases, and affects 3.4-22.9/10,000 individuals worldwide (1). -
Chromosome Integrity in Saccharomyces Cerevisiae: the Interplay of DNA Replication Initiation Factors, Elongation Factors, and Origins
Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Chromosome integrity in Saccharomyces cerevisiae: the interplay of DNA replication initiation factors, elongation factors, and origins Dongli Huang1,2 and Douglas Koshland1,3 1Howard Hughes Medical Institute, Carnegie Institution of Washington, Department of Embryology, Baltimore, Maryland 21210, USA; 2Johns Hopkins University, Department of Biology, Baltimore, Maryland 21218, USA The integrity of chromosomes during cell division is ensured by both trans-acting factors and cis-acting chromosomal sites. Failure of either these chromosome integrity determinants (CIDs) can cause chromosomes to be broken and subsequently misrepaired to form gross chromosomal rearrangements (GCRs). We developed a simple and rapid assay for GCRs, exploiting yeast artificial chromosomes (YACs) in Saccharomyces cerevisiae. We used this assay to screen a genome-wide pool of mutants for elevated rates of GCR. The analyses of these mutants define new CIDs (Orc3p, Orc5p, and Ycs4p) and new pathways required for chromosome integrity in DNA replication elongation (Dpb11p), DNA replication initiation (Orc3p and Orc5p), and mitotic condensation (Ycs4p). We show that the chromosome integrity function of Orc5p is associated with its ATP-binding motif and is distinct from its function in controlling the efficiency of initiation of DNA replication. Finally, we used our YAC assay to assess the interplay of trans and cis factors in chromosome integrity. Increasing the number of origins on a YAC suppresses GCR formation in our dpb11 mutant but enhances it in our orc mutants. This result provides potential insights into the counterbalancing selective pressures necessary for the evolution of origin density on chromosomes. -
In Vivo Interactions of Archaeal Cdc6 Orc1 and Minichromosome
In vivo interactions of archaeal Cdc6͞Orc1 and minichromosome maintenance proteins with the replication origin Fujihiko Matsunaga*, Patrick Forterre*, Yoshizumi Ishino†, and Hannu Myllykallio*§ *Institut de Ge´ne´ tique et Microbiologie, Universite´de Paris-Sud, 91405 Orsay, France; and †Department of Molecular Biology, Biomolecular Engineering Research Institute, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan Communicated by Bruce W. Stillman, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, July 25, 2001 (received for review May 25, 2001) Although genome analyses have suggested parallels between basis of asymmetry in base composition between leading and archaeal and eukaryotic replication systems, little is known about lagging strands (10, 11). In Pyrococcus abyssi, the location of the the DNA replication mechanism in Archaea. By two-dimensional predicted origin coincides with an early replicating chromosomal gel electrophoreses we positioned a replication origin (oriC) within segment of 80 kb identified by radioactive labeling of chromo- 1 kb in the chromosomal DNA of Pyrococcus abyssi, an anaerobic somal DNA in cultures released from a replication block (12). hyperthermophile, and demonstrated that the oriC is physically Our in silico and labeling data also allowed us to conclude that linked to the cdc6 gene. Our chromatin immunoprecipitation as- the hyperthermophilic archaeon P. abyssi uses a single bidirec- says indicated that P. abyssi Cdc6 and minichromosome mainte- tional origin to replicate its genome. We proposed that this origin nance (MCM) proteins bind preferentially to the oriC region in the would correspond to the long intergenic region conserved in all exponentially growing cells. Whereas the oriC association of MCM three known Pyrococcus sp. -
Signature of Progression and Negative Outcome in Colorectal Cancer
Oncogene (2010) 29, 876–887 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc ORIGINAL ARTICLE A ‘DNA replication’ signature of progression and negative outcome in colorectal cancer M-J Pillaire1,7, J Selves2,7, K Gordien2, P-A Gouraud3, C Gentil3, M Danjoux2,CDo3, V Negre4, A Bieth1, R Guimbaud2, D Trouche5, P Pasero6,MMe´chali6, J-S Hoffmann1 and C Cazaux1 1Genetic Instability and Cancer Group, Department Biology of Cancer, Institute of Pharmacology and Structural Biology, UMR5089 CNRS, University of Toulouse, University Paul Sabatier, Toulouse, France; 2INSERM U563, Federation of Digestive Cancerology and Department of Anatomo-pathology, University of Toulouse, University Paul Sabatier, Toulouse, France; 3Service of Epidemiology, INSERM U558, Faculty of Medicine, University of Toulouse, University Paul Sabatier, Alle´es Jules Guesde, Toulouse, France; 4aCGH GSO Canceropole Platform, INSERM U868, Val d’Aurelle, Montpellier, France; 5Laboratory of Cellular and Molecular Biology of Cell Proliferation Control, UMR 5099 CNRS, University of Toulouse, University Paul Sabatier, Toulouse, France and 6Institute of Human Genetics UPR1142 CNRS, Montpellier, France Colorectal cancer is one of the most frequent cancers Introduction worldwide. As the tumor-node-metastasis (TNM) staging classification does not allow to predict the survival of DNA replication in normal cells is regulated by an patients in many cases, additional prognostic factors are ‘origin licensing’ mechanism that ensures that it occurs needed to better forecast their outcome. Genes involved in just once per cycle. Once cells enter the S-phase, the DNA replication may represent an underexplored source stability of DNA replication forks must be preserved to of such prognostic markers. -
Chromosome Duplication in Saccharomyces Cerevisiae
| YEASTBOOK GENOME ORGANIZATION AND INTEGRITY Chromosome Duplication in Saccharomyces cerevisiae Stephen P. Bell*,1 and Karim Labib†,1 *Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and yMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, School of Life Sciences, University of Dundee, DD1 5EH, United Kingdom ORCID ID: 0000-0002-2876-610X (S.P.B.) ABSTRACT The accurate and complete replication of genomic DNA is essential for all life. In eukaryotic cells, the assembly of the multi-enzyme replisomes that perform replication is divided into stages that occur at distinct phases of the cell cycle. Replicative DNA helicases are loaded around origins of DNA replication exclusively during G1 phase. The loaded helicases are then activated during S phase and associate with the replicative DNA polymerases and other accessory proteins. The function of the resulting replisomes is monitored by checkpoint proteins that protect arrested replisomes and inhibit new initiation when replication is inhibited. The replisome also coordinates nucleosome disassembly, assembly, and the establishment of sister chromatid cohesion. Finally, when two replisomes converge they are disassembled. Studies in Saccharomyces cerevisiae have led the way in our understanding of these processes. Here, we review our increasingly molecular understanding of these events and their regulation. KEYWORDS DNA replication; cell cycle; chromatin; chromosome duplication; genome stability;