Novel Insights Into Extrachromosomal DNA: Redefining the Onco-Drivers Of

Total Page:16

File Type:pdf, Size:1020Kb

Novel Insights Into Extrachromosomal DNA: Redefining the Onco-Drivers Of Gu et al. Journal of Experimental & Clinical Cancer Research (2020) 39:215 https://doi.org/10.1186/s13046-020-01726-4 REVIEW Open Access Novel insights into extrachromosomal DNA: redefining the onco-drivers of tumor progression Xiang Gu1,2†, Jie Yu1,2†, Peiwei Chai1,2†, Shengfang Ge1,2* and Xianqun Fan1,2* Abstract Extrachromosomal DNA (ecDNA), gene-encoding extrachromosomal particles of DNA, is often present in tumor cells. Recent studies have revealed that oncogene amplification via ecDNA is widespread across a diverse range of cancers. ecDNA is involved in increasing tumor heterogeneity, reverting tumor phenotypes, and enhancing gene expression and tumor resistance to chemotherapy, indicating that it plays a significant role in tumorigenesis. In this review, we summarize the characteristics and genesis of ecDNA, connect these characteristics with their concomitant influences on tumorigenesis, enumerate the oncogenes encoded by ecDNA in multiple cancers, elaborate the roles of ecDNA in tumor pathogenesis and progression, and propose the considerable research and therapeutic prospects of ecDNA in cancer. Keywords: Extrachromosomal DNA, Oncogene, Tumorigenesis Background base pairs [9, 10]. These particles have been proved to be Genetic material guarantees the transmission of genetic circular by biophysical methods and DNA sequencing. information from parents to their offspring. With the Verhaak et al. divided these particles into two types based exception of some viruses, DNA is the carrier of genetic on the size and resultant functions [11]. Small particles, material, which was first identified by Frederick Griffith in which are called extrachromosomal circular DNA a Streptococcus pneumoniae transformation experiment (eccDNA), are usually less than 1 kb; consequently, they [1–3]. DNA is present in a compacted and dynamic com- are undetectable by light microscopy and lack full-length plex called chromatin in the cell nucleus. During the genes [12–14]. Investigations of eccDNA have revealed its metaphase of cell division, chromatin organizes into highly association with aging, as eccDNA containing ribosomal condensed chromosomes [4]. DNA also exists in organ- DNA genes accumulates in old cells and contributes to elles including mitochondria and chloroplasts, which the aging of yeast cells. The probable mechanism is de- probably evolved from microorganisms such as α- scribed by the titration hypothesis, which indicates that proteobacteria and cyanobacterium invading host cells the accumulated eccDNA might precipitate the compo- and starting a symbiotic life form [5–8]. In addition, it has nents of replication and/or transcription elements, and been reported that extrachromosomal particles of DNA eventually trigger the senescence and the eventual death exist, the size of which varies from dozens to millions of of old cells [15, 16]. Cohen et al. revealed that small poly- dispersed circular DNA (spcDNA), one type of eccDNA, is related to chromosomal instability (CIN), which is a * Correspondence: [email protected]; [email protected] †Xiang Gu, Jie Yu and Peiwei Chai contributed equally to this work. characteristic of malignant cells since the spcDNA mole- 1Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong cules were frequently found in either intrinsically unstable University School of Medicine, Shanghai 20025, P. R. China cells including tumor cells or in cells exposed to an Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gu et al. Journal of Experimental & Clinical Cancer Research (2020) 39:215 Page 2 of 10 external carcinogen treatment, indicating that spcDNA ecDNA is acentric with uneven segregation at cell division may be a possible marker of CIN [17, 18]. Extrachromo- The centromere, which consists of repetitive DNA, is somal DNA (ecDNA), the focus of this review, includes the region where sister chromatids remain connected relatively large particles generally ranging from 1 to 3 Mb, until mitosis and has a unique histone—CenpA. The with a median size of 1.26 Mb, which are therefore visible centromere is the ‘landing platform’ for the kinetochore, by light microscopy and encompass whole genes as well as a large protein structure that binds to microtubules in regulatory regions [11, 19–21]. ecDNA was first discov- mitosis and ensures accurate sister chromatid separation ered as paired small chromatin bodies in neuroblastoma and chromosome segregation [40, 41]. Because centro- (NB) cells called double minutes (DMs) [10]. Jack et al. meres lack ecDNA, ecDNA segregates unevenly at cell performed a scanning electron microscopy (SEM) study of division, allowing daughter cells to possess up to twice DMs and demonstrated that the identical sister minutes as many ecDNA particles as their corresponding mother appeared as two spherical chromatin bodies intercon- cells [31]. Uneven segregation of ecDNA leads to genetic nected by chromatin fibers [22]. Later, Turner et al. per- material distribution uncertainty, which may result in a formed whole-genome sequencing (WGS), structural rapid increase in oncogene copy number in a short modeling and cytogenetic analyses of 17 different cancer period and increase intratumoral heterogeneity, enhan- types and found that only 30% of ecDNA in tumor cells is cing tumor fitness to changing environments [32]. paired; thus, ecDNA is used as a general term to refer to large, gene-containing extrachromosomal particles of The resultant heterogeneity in cancer with ecDNA DNA, including both DMs and single body forms, with deCarvalho et al. revealed that ecDNA presented single minutes showing no apparent partners nearby. The divergent inheritance patterns and clonal selection existence of ecDNA has been confirmed in various types dynamics through an extensive genomic and transcrip- of cancers and cancer cell lines [23]. Unlike the smaller tomic analysis of 13 glioblastoma (GBM) tumor samples eccDNA particles, ecDNA is sufficiently large enough to and neurosphere-forming cultures and orthotopic xeno- contain one or multiple full genes, including oncogenes, graft models established from these samples, inferring and oncogenes located on ecDNA were first reported to the uneven inheritance of ecDNA between offspring map MYCN to DMs in NB [24]. Subsequent studies con- cells, which may explain the rapidly enhanced genomic firmed the existence of oncogene amplification on ecDNA heterogeneity during GBM evolution [42]. Xu et al. in multiple types of cancer [25–28]. Although oncogene characterized DMs in paired diagnosis and relapse amplification via ecDNA has been recognized, ecDNA tumors from 4 GBM patients and found that identical was thought to be rare in cancer for a long time; therefore, oncogenes could amplify on different DMs at diagnosis the role of ecDNA in tumorigenesis has received little at- and relapse, reflecting the primed evolution and rapidly tention [29, 30]. This perception was maintained until an increasing heterogeneity of DMs [43]. unbiased approach was developed to detect ecDNA by in- tegrating WGS and cytogenetic image analysis. The results ecDNA can be eliminated by micronucleus formation showed that oncogene amplification via ecDNA is wide- Oncogenes on DMs are unstable, and DMs can be elimi- spread in different cancers, thus arousing people’s interest nated in tumor cells by incorporating DMs into the in extrachromosomal oncogene amplification when cytoplasmic micronucleus when they are exposed to exploring tumorigenesis [23]. In this review, we focus on DNA replication inhibitors such as a low dose of the characteristics and genesis of ecDNA and emphasize hydroxyurea (HU) and radiation [34, 35]. In addition, in- its role in tumorigenesis. hibition of ERK1/2 activation, one of the main mitogen- activated protein kinase (MAPK) signaling pathways, also breaks DNA to eliminate DMs [36]. Acentric DMs Characteristics of ecDNA were found to segregate by adhering to the chromosome The rapid development of new techniques enables deter- arm during cell division, a process is called ‘hitchhiking’ mination of the unique characteristics of ecDNA. Com- (Fig. 1.a). When cells are exposed to a low dose of HU, pared to chrDNA, ecDNA is acentric with uneven DMs aggregate and detach from the chromosome; sub- segregation at cell division, leading to increased intratu- sequently, the aggregated DMs generate micronuclei moral heterogeneity and enhanced fitness to changing (Fig. 1.b). The
Recommended publications
  • The Characterization of a Heat-Activated Retrotransposon ONSEN and the Effect of Zebularine in Adzuki Bean and Title Soybean
    The characterization of a heat-activated retrotransposon ONSEN and the effect of zebularine in adzuki bean and Title soybean Author(s) BOONJING, PATWIRA Citation 北海道大学. 博士(生命科学) 甲第14157号 Issue Date 2020-06-30 DOI 10.14943/doctoral.k14157 Doc URL http://hdl.handle.net/2115/82053 Type theses (doctoral) File Information PATWIRA_BOONJING.pdf Instructions for use Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP Thesis for Ph.D. Degree The characterization of a heat-activated retrotransposon ONSEN and the effect of zebularine in adzuki bean and soybean 「アズキとダイズにおける高温活性型レトロトランス ポゾン ONSEN の特徴とゼブラリンの効果について」 by Patwira Boonjing Graduate School of Life Science Hokkaido University June 2020 Thesis for Ph.D. Degree The characterization of a heat-activated retrotransposon ONSEN and the effect of zebularine in adzuki bean and soybean 「アズキとダイズにおける高温活性型レトロトランス ポゾン ONSEN の特徴とゼブラリンの効果について」 by Patwira Boonjing Graduate School of Life Science Hokkaido University June 2020 2 Abstract The Ty1/copia-like retrotransposon ONSEN is conserved among Brassica species, as well as in beans, including adzuki bean (Vigna angularis (Willd.) Ohwi & Ohashi) and soybean (Glycine max (L.) Merr.), which are the economically important crops in Japan. ONSEN has acquired a heat-responsive element that is recognized by plant-derived heat stress defense factors, resulting in transcribing and producing the full-length extrachromosomal DNA under conditions with elevated temperatures. DNA methylation plays an important role in regulating the activation of transposons in plants. Therefore, chemical inhibition of DNA methyltransferases has been utilized to study the effect of DNA methylation on transposon activation. To understand the effect of DNA methylation on ONSEN activation, Arabidopsis thaliana, adzuki bean, and soybean plants were treated with zebularine, which is known to be an effective chemical demethylation agent.
    [Show full text]
  • Mobile Genetic Elements in Streptococci
    Curr. Issues Mol. Biol. (2019) 32: 123-166. DOI: https://dx.doi.org/10.21775/cimb.032.123 Mobile Genetic Elements in Streptococci Miao Lu#, Tao Gong#, Anqi Zhang, Boyu Tang, Jiamin Chen, Zhong Zhang, Yuqing Li*, Xuedong Zhou* State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China. #Miao Lu and Tao Gong contributed equally to this work. *Address correspondence to: [email protected], [email protected] Abstract Streptococci are a group of Gram-positive bacteria belonging to the family Streptococcaceae, which are responsible of multiple diseases. Some of these species can cause invasive infection that may result in life-threatening illness. Moreover, antibiotic-resistant bacteria are considerably increasing, thus imposing a global consideration. One of the main causes of this resistance is the horizontal gene transfer (HGT), associated to gene transfer agents including transposons, integrons, plasmids and bacteriophages. These agents, which are called mobile genetic elements (MGEs), encode proteins able to mediate DNA movements. This review briefly describes MGEs in streptococci, focusing on their structure and properties related to HGT and antibiotic resistance. caister.com/cimb 123 Curr. Issues Mol. Biol. (2019) Vol. 32 Mobile Genetic Elements Lu et al Introduction Streptococci are a group of Gram-positive bacteria widely distributed across human and animals. Unlike the Staphylococcus species, streptococci are catalase negative and are subclassified into the three subspecies alpha, beta and gamma according to the partial, complete or absent hemolysis induced, respectively. The beta hemolytic streptococci species are further classified by the cell wall carbohydrate composition (Lancefield, 1933) and according to human diseases in Lancefield groups A, B, C and G.
    [Show full text]
  • World Journal of Advanced Research and Reviews
    World Journal of Advanced Research and Reviews, 2020, 08(02), 279–284 World Journal of Advanced Research and Reviews e-ISSN: 2581-9615, Cross Ref DOI: 10.30574/wjarr Journal homepage: https://www.wjarr.com (REVIEW ARTICLE) Fundamentals of extrachromosomal circular DNA in human cells - Genetic activities as regards cancer promotion alongside chromosomal DNA Reinhard H. Dennin * Formerly: Department of Infectious Diseases and Microbiology, University of Lübeck, UKSH, Campus Lübeck, Germany. Publication history: Received on 17 November 2020; revised on 24 November 2020; accepted on 25 November 2020 Article DOI: https://doi.org/10.30574/wjarr.2020.8.2.0442 Abstract In addition to chromosomal DNA (chr-DNA) and mitochondrial DNA, eukaryotic cells contain extrachromosomal DNA (ec-DNA). Analysed extrachromosomal circular DNA (ecc-DNA) accounts for up to 20% of the total cellular DNA. Ecc- DNAs contain coding and non-coding sequences originating from chr-DNA and mobile genetic elements (MGEs). MGEs include sequences such as transposons, which have the potential to move between different and the same DNA molecules, thereby, for example, causing rearrangements and inactivation of genes. Ecc DNAs have aroused interest in diseases such as malignancies and diagnostic procedures relating to this. A database to collect ecc-DNA has been established. Investigations are needed to find possible differences in sequences of chr-DNA after sequencing the whole cellular DNA (WCD), namely: chr-DNA plus ec-/ecc-DNA compared to chr-DNA, which is separated from ec-/ecc-DNA. Standards for sequencing protocols of WCD have to be developed that also reveal the sequences of ecc-DNA; this concerns “single-cell genomics” in particular.
    [Show full text]
  • Genome-Wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells
    Journal of Visualized Experiments www.jove.com Video Article Genome-wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells Henrik D. Møller1, Rasmus K. Bojsen2, Chris Tachibana3, Lance Parsons4, David Botstein5, Birgitte Regenberg1 1 Department of Biology, University of Copenhagen 2 National Veterinary Institute, Technical University of Denmark 3 Group Health Research Institute 4 Lewis-Sigler Institute for Integrative Genomics, Princeton University 5 Calico Life Sciences LLC Correspondence to: Birgitte Regenberg at [email protected] URL: https://www.jove.com/video/54239 DOI: doi:10.3791/54239 Keywords: Molecular Biology, Issue 110, Circle-Seq, deletion, eccDNA, rDNA, ERC, ECE, microDNA, minichromosomes, small polydispersed circular DNA, spcDNA, double minute, amplification Date Published: 4/4/2016 Citation: Møller, H.D., Bojsen, R.K., Tachibana, C., Parsons, L., Botstein, D., Regenberg, B. Genome-wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells. J. Vis. Exp. (110), e54239, doi:10.3791/54239 (2016). Abstract Extrachromosomal circular DNAs (eccDNAs) are common genetic elements in Saccharomyces cerevisiae and are reported in other eukaryotes as well. EccDNAs contribute to genetic variation among somatic cells in multicellular organisms and to evolution of unicellular eukaryotes. Sensitive methods for detecting eccDNA are needed to clarify how these elements affect genome stability and how environmental and biological factors induce their formation in eukaryotic cells. This video presents a sensitive eccDNA-purification method called Circle-Seq. The method encompasses column purification of circular DNA, removal of remaining linear chromosomal DNA, rolling-circle amplification of eccDNA, deep sequencing, and mapping. Extensive exonuclease treatment was required for sufficient linear chromosomal DNA degradation. The rolling-circle amplification step by φ29 polymerase enriched for circular DNA over linear DNA.
    [Show full text]
  • Double Minute Chromosomes in Glioblastoma Multiforme Are Revealed by Precise Reconstruction of Oncogenic Amplicons
    Published OnlineFirst August 12, 2013; DOI: 10.1158/0008-5472.CAN-13-0186 Cancer Tumor and Stem Cell Biology Research Double Minute Chromosomes in Glioblastoma Multiforme Are Revealed by Precise Reconstruction of Oncogenic Amplicons J. Zachary Sanborn1,2,Sofie R. Salama2,3, Mia Grifford2, Cameron W. Brennan4, Tom Mikkelsen6, Suresh Jhanwar5, Sol Katzman2, Lynda Chin7, and David Haussler2,3 Abstract DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrange- ments and copy number in tumor genomes. Here, we describe the development of methods to compute copy number and detect structural variants to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard, short-read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes in these tumors. Further, we find that some samples harbor multiple circular amplicons and, in some cases, further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization analysis offered an initial confirmation of the presence of double minute chromosomes. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one double minute chromosome offered additional support for our local tumor genome assemblies, and identified the birth of a novel exon made possible through rearranged sequences present in the double minute chromosomes. Our method was also useful for analysis of a larger set of glioblastoma multiforme tumors for which exome sequencing data are available, finding evidence for oncogenic double minute chromosomes in more than 20% of clinical specimens examined, a frequency consistent with previous estimates.
    [Show full text]
  • Single Cell Multi-Omics Analysis of Chromothriptic Medulloblastoma Highlights Genomic and Transcriptomic Consequences of Genome Instability
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.25.449944; this version posted June 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Single cell multi-omics analysis of chromothriptic medulloblastoma highlights genomic and transcriptomic consequences of genome instability R. Gonzalo Parra*1,2, Moritz J Przybilla*1,2,3, Milena Simovic*4,5, Hana Susak*1,2, Manasi Ratnaparkhe4, John KL Wong6, Verena Körber7, Philipp Mallm8, Martin Sill9, Thorsten Kolb4, Rithu Kumar4, Nicola Casiraghi1,2, David R Norali Ghasemi9, Kendra Korinna Maaß9, Kristian W Pajtler9,10, Anna Jauch11, Andrey Korshunov12, Thomas Höfer7, Marc Zapatka6, Stefan M Pfister9,10, Oliver Stegle*#1,2,3, Aurélie Ernst*#4 *These authors contributed equally (author order alphabetically) We suggest to define an explicit order among the first authors at a later stage, to make it as fair as possible also in the line of the revisions. #Corresponding authors 1European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany. 2 Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Wellcome Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK 4 Group “Genome Instability in Tumors”, German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Faculty of Biosciences, Heidelberg University 6 Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany 7 Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Single-cell Open Lab, German Cancer Research Center (DKFZ) and Bioquant, Heidelberg, Germany 9 Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    [Show full text]
  • A Acentric Fragment Linear One Telomere Radiation One Broken End Endonuclease Break-Inducing Mutagen
    Chromosome Res https://doi.org/10.1007/s10577-020-09636-z REVIEW Mechanisms driving acentric chromosome transmission Brandt Warecki & William Sullivan Received: 2 June 2020 /Revised: 16 July 2020 /Accepted: 19 July 2020 # Springer Nature B.V. 2020 Abstract The kinetochore-microtubule association is a Keywords Acentric . chromosome fragment . mitosis . core, conserved event that drives chromosome transmis- microtubules . double minutes . genome stability sion during mitosis. Failure to establish this association on even a single chromosome results in aneuploidy Abbreviations leading to cell death or the development of cancer. APC/C Anaphase-promoting complex However, although many chromosomes lacking centro- PtK cells Potorous tridactylus cells meres, termed acentrics, fail to segregate, studies in a UFBs Ultrafine DNA bridges number of systems reveal robust alternative mecha- CHMP4C Charged multivesicular body nisms that can drive segregation and successful pole- protein 4C ward transport of acentrics. In contrast to the canonical ESCRT-III Endosomal sorting complexes mechanism that relies on end-on microtubule attach- required for transport-III ments to kinetochores, mechanisms of acentric trans- mission largely fall into three categories: direct attach- ments to other chromosomes, kinetochore-independent lateral attachments to microtubules, and long-range teth- er-based attachments. Here, we review these “non-ca- Kinetochore-microtubule interactions drive nonical” methods of acentric chromosome transmission. poleward chromosome transmission Just as the discovery and exploration of cell cycle checkpoints provided insight into both the origins of In order to produce genetically identical daughter cells cancer and new therapies, identifying mechanisms and following mitosis, a cell must first duplicate its genome structures specifically involved in acentric segregation and then equally partition genetic material to its daugh- may have a significant impact on basic and applied ter cells through chromatid segregation.
    [Show full text]
  • Hyper Telomere Recombination Accelerates Replicative Senescence and May Promote Premature Aging
    Hyper telomere recombination accelerates replicative senescence and may promote premature aging R. Tanner Hagelstroma,b, Krastan B. Blagoevc,d, Laura J. Niedernhofere, Edwin H. Goodwinf, and Susan M. Baileya,1 aDepartment of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1618; bPharmaceutical Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004; cNational Science Foundation, Arlington, VA 22230; dDepartment of Physics Cavendish Laboratory, Cambridge University, Cambridge CB3 0HE, United Kingdom; eDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine and Cancer Institute, Pittsburgh, PA 15261; and fKromaTiD Inc., Fort Collins, CO 80524 Edited* by José N. Onuchic, University of California San Diego, La Jolla, CA, and approved August 3, 2010 (received for review May 7, 2010) Werner syndrome and Bloom syndrome result from defects in the cell-cycle arrest known as senescence (12). Most human tissues lack RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and sufficient telomerase activity to maintain telomere length through- display premature aging phenotypes. Similarly, XFE progeroid out life, limiting cell division potential. The majority of cancers syndrome results from defects in the ERCC1-XPF DNA repair endo- circumvent this tumor-suppressor mechanism by reactivating telo- nuclease. To gain insight into the origin of cellular senescence and merase (13), thus removing telomere shortening as a barrier to human aging, we analyzed the dependence of sister chromatid continuous proliferation. In some situations, a recombination- exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telo- based mechanism known as “alternative lengthening of telomeres” meric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, (ALT) maintains telomere length in the absence of telomerase (14).
    [Show full text]
  • Chapter 9 Genetics Chromosome Genes • DNA RNA Protein Flow Of
    Genetics Chapter 9 Topics • Genome - the sum total of genetic - Genetics information in a organism - Flow of Genetics/Information • Genotype - the A's, T's, G's and C's - Regulation • Phenotype - the physical - Mutation characteristics that are encoded - Recombination – gene transfer within the genome Examples of Eukaryotic and Prokaryotic Genomes Chromosome • Prokaryotic ( E. coli ~ 4,288 genes) – 1 circular chromosome ± extrachromosomal DNA ( plasmids ) • Eukaryotic (humans ~ 20 -25,000 genes) – Many paired chromosomes ± extrachromosomal DNA ( Mitochondria or Chloroplast ) • Subdivided into basic informational packets called genes Genes Flow of Genetics/Information • Three categories The Central Dogma –Structural - genes that code for • DNA RNA Protein proteins –Regulatory - genes that control – Replication - copy DNA gene expression – Transcription - make mRNA – Translation - make protein –Encode for RNA - non-mRNA 1 Replication Transcription & Translation DNA • Structure • Replication • Universal Code & Codons Escherichia coli with its emptied genome! Structure • Nucleotide – Phosphate – Deoxyribose sugar – Nitrogenous base • Double stranded helix – Antiparallel arrangement Versions of the DNA double helix Nitrogenous bases 5’ 3’ • Purines –Adenine 3’ 5’ –Guanine • Pyrimidines –Thymine –Cytosine 2 Replication • Semiconservative - starts at the Origin of Replication • Enzymes • Helicase • Dna Pol III • DNA Pol I • Primase • Gyrase • Ligase • Leading strand • Lagging strand – Okazaki fragments The function of important enzymes involved
    [Show full text]
  • Discordant Inheritance of Chromosomal and Extrachromosomal DNA Elements 2 Contributes to Dynamic Disease Evolution in Glioblastoma
    bioRxiv preprint doi: https://doi.org/10.1101/081158; this version posted June 27, 2017. 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. 1 Discordant inheritance of chromosomal and extrachromosomal DNA elements 2 contributes to dynamic disease evolution in glioblastoma 3 Ana C. deCarvalho1*†, Hoon Kim2*, Laila M. Poisson3, Mary E. Winn4, Claudius 4 Mueller5, David Cherba4, Julie Koeman6, Sahil Seth7, Alexei Protopopov7, Michelle 5 Felicella8, Siyuan Zheng9, Asha Multani10, Yongying Jiang7, Jianhua Zhang7, Do-Hyun 6 Nam11, 12, 13 Emanuel F. Petricoin5, Lynda Chin2, 7, Tom Mikkelsen1, 14†, Roel G.W. 7 Verhaak2† 8 9 1Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA. 10 2The Jackson Laboratory for Genomic Medicine, Farmington, CT 06130, USA. 11 3Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI 48202, USA. 12 4Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI 13 49503, USA. 14 5Center for Applied Proteomics and Personalized Medicine, George Mason University, 15 Manassas, VA, USA 16 6Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, MI 17 49503, USA. 18 7Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer 19 Center, Houston, TX 77030, USA. 20 8Department of Pathology, Henry Ford Hospital, Detroit, MI 48202, USA. 21 9Deptartment of Genetics, The University of Texas MD Anderson Cancer Center, 22 Houston,
    [Show full text]
  • Homogeneously Staining Regions Or Double Minute Chromosomes in Leukemia Abolfazl Movafagh Phd, Associate Professor
    BRIEF COMMUNICATION IJBC 2012;2: 101-102 Homogeneously Staining Regions or Double Minute Chromosomes in Leukemia Abolfazl Movafagh PhD, Associate Professor Corresponding Author:Department of Medical Genetics, Shahid Beheshti University of Medical Sciences ,Tehran, Iran, Fax +98(21) 2240067 +98-21-23872572; E mail: [email protected] Submit: 10-11-2010, Accept: 15-02-2011 Homogeneously Staining Regions (HSRs) or chromosomes. The presence of DMs among Double Minute Chromosomes (DMs) are the leukemia patients in our laboratory has also been cytogenetic hallmarks of genomic amplification in observed in other parts of the world. cancers and derive from the breakpoint region of The identification of two new cases of DMs translocation event. The relationship of DMs/HSRs presented here together with large Mitelman and malignancies seems to be well established database (http://cgapanci.nih.gov/chromosomes/ and indeed DMs/ HSRs have not, so far, been Mitelman) and other pertinent website reports observed in non malignant cells. DMs/ HSRs were suggest an association with leukemia. However, first described in a direct preparation of cells from further studies and accumulation of new cases a patient with untreated bronchogenic carcinoma are needed in the hope of defining it as a specific (DMs originating from chromosome 19). DMs are abnormality in the field of leukemia. small chromatin particles that represent a form of extra chromosomal gene amplification and a References mechanism for unregulated oncogene expression 1. Storlazzi CT, Lonoce A, Maria CG, Trombetta D, which is generally associated with a poor prognosis. Daddabbo P, Daniele G, Labba A A, et al. Gene Gene amplification causes an increase in the gene amplificatIon as double minutes or homogeneously copy number and, subsequently, elevates the stain regions in solid tumors: Origin and structure.
    [Show full text]
  • Extrachromosomal DNA in Genome (In)Stability – Role of Telomeres
    ORIGINAL SCIENTIFIC PAPER Croat. Chem. Acta 2016, 89(2), 175–181 Published online: June 17, 2016 DOI: 10.5562/cca2841 Extrachromosomal DNA in Genome (in)Stability – Role of Telomeres Lucia Nanić, Sanda Ravlić, Ivica Rubelj* Department of Molecular Biology, Ruđer Bošković Institute, Bijenička c. 54, 10000 Zagreb, Croatia * Corresponding author’s e-mail address: [email protected] RECEIVED: February 22, 2016 REVISED: May 5, 2016 ACCEPTED: May 9, 2016 THIS PAPER IS DEDICATED TO THE LOVING MEMORY OF IVANA WEYGAND-ĐURAŠEVIĆ (1952 – 2014) Abstract: Eukaryotic genome consists of long linear chromosomes. It is complex in its content and has dynamic features. It mostly consists of non-coding DNA of various repeats, often prone to recombination including creation of extrachromosomal DNA which can be re-integrated into distant parts of the genome, often in different chromosome. These events are usually part of normal genome function enabling molecular response to changes in the cell or organism’s environment and enabling their evolutionary development as well. These mechanisms also contribute to genome instability as in the case of abnormal immortalization like in cancer cells. Telomeres are among most important repetitive sequences, located at the end of linear chromosomes. They serve as guardians of genome stability but they also have dynamic features playing important role in cell aging and immortalization, both as chromosomal components or as extrachromosomal DNA. Also, recombination events on telomeres provide plausible explanation for stochastic nature of cell senescence, a phenomenon unjustly overlooked in broader literature. Keywords: extrachromosomal DNA, genome stability, satellite DNA, telomeres, cell aging. EUKARYOTIC GENOME THE REPETITIVE DNA CONTENT OF THE GENOME IZE of eukaryotic genomes often are not correlated with S their genetic complexity.
    [Show full text]