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Olatunde OZ, Yong J, Lu C, Ming Y. A Review on Shikonin and Its Derivatives as Potent Anticancer Agents Targeted against Topoisomerases. Curr Med Chem 2023; 31:CMC-EPUB-129356. [PMID: 36752292 DOI: 10.2174/0929867330666230208094828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 11/12/2022] [Accepted: 11/30/2022] [Indexed: 02/09/2023]
Abstract
The topoisomerases (TOPO) play indispensable roles in DNA metabolism, by regulating the topological state of DNA. Topoisomerase I and II are the well-established drug-targets for the development of anticancer agents and antibiotics. These drugs-targeting enzymes have been used to establish the relationship between drug-stimulated DNA cleavable complex formation and cytotoxicity. Some anticancer drugs (such as camptothecin, anthracyclines, mitoxantrone) are also widely used as Topo I and Topo II inhibitors, but the poor water solubility, myeloma suppression, dose-dependent cardiotoxicity, and multidrug resistance (MDR) limited their prolong use as therapeutics. Also, most of these agents displayed selective inhibition only against Topo I or II. In recent years, researchers focus on the design and synthesis of the dual Topo I and II inhibitors, or the discovery of the dual Topo I and II inhibitors from natural products. Shikonin (a natural compound with anthraquinone skeleton, isolated from the roots of Lithospermum erythrorhizon) has drawn much attention due to its wide spectrum of anticancer activities, especially due to its dual Topo inhibitive performance, and without the adverse side effects, and different kinds of shikonin derivatives have been synthesized as TOPO inhibitors for the development of anticancer agents. In this review, the progress of the shikonin and its derivatives together with their anticancer activities, anticancer mechanism, and their structure-activity relationship (SAR) was comprehensively summarized by searching the CNKI, PubMed, Web of Science, Scopus, and Google Scholar databases.
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Affiliation(s)
- Olagoke Zacchaeus Olatunde
- Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian,350002, China
| | - Jianping Yong
- Xiamen Institute of Rare-earth Materials, Chinese Academy of Sciences, Xiamen, Fujian, 361021, China
| | - Canzhong Lu
- Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian,350002, China
- Xiamen Institute of Rare-earth Materials, Chinese Academy of Sciences, Xiamen, Fujian, 361021, China
| | - Yanlin Ming
- Fujian Institute of Subtropical Botany, Xiamen, Fujian, 361006, China
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2
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The Role of PARP1 and PAR in ATP-Independent Nucleosome Reorganisation during the DNA Damage Response. Genes (Basel) 2022; 14:genes14010112. [PMID: 36672853 PMCID: PMC9859207 DOI: 10.3390/genes14010112] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 12/31/2022] Open
Abstract
The functioning of the eukaryotic cell genome is mediated by sophisticated protein-nucleic-acid complexes, whose minimal structural unit is the nucleosome. After the damage to genomic DNA, repair proteins need to gain access directly to the lesion; therefore, the initiation of the DNA damage response inevitably leads to local chromatin reorganisation. This review focuses on the possible involvement of PARP1, as well as proteins acting nucleosome compaction, linker histone H1 and non-histone chromatin protein HMGB1. The polymer of ADP-ribose is considered the main regulator during the development of the DNA damage response and in the course of assembly of the correct repair complex.
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3
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Du Y, Yamaguchi H, Hsu JL, Hung MC. PARP inhibitors as precision medicine for cancer treatment. Natl Sci Rev 2017. [DOI: 10.1093/nsr/nwx027] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AbstractPersonalized or precision medicine is an emerging treatment approach tailored to individuals or certain groups of patients based on their unique characteristics. These types of therapies guided by biomarkers tend to be more effective than traditional approaches, especially in cancer. The inhibitor against poly (ADP-ribose) polymerase (PARP), olaparib (Lynparza, AstraZeneca), which was approved by the US Food and Drug Administration (FDA) in 2014, demonstrated efficacy specifically for ovarian cancer patients harboring mutations in BRCA genes, which encode proteins in DNA double-strand break repairs. However, the response to PARP inhibitors has been less encouraging in other cancer types that also carry defects in the BRCA genes. Thus, furthering our understanding of the underlying mechanism of PARP inhibitors and resistance is critical to improve their efficacy. In this review, we summarize the results of preclinical studies and the clinical application of PARP inhibitors, and discuss the future direction of PARP inhibitors as a potential marker-guided personalized medicine for cancer treatment.
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Affiliation(s)
- Yi Du
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030
| | - Hirohito Yamaguchi
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030
| | - Jennifer L. Hsu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 40402
- Department of Biotechnology, Asia University, Taichung 41354
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 40402
- Department of Biotechnology, Asia University, Taichung 41354
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Hazra J, Mukherjee P, Ali A, Poddar S, Pal M. Engagement of Components of DNA-Break Repair Complex and NFκB in Hsp70A1A Transcription Upregulation by Heat Shock. PLoS One 2017; 12:e0168165. [PMID: 28099440 PMCID: PMC5242496 DOI: 10.1371/journal.pone.0168165] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 11/26/2016] [Indexed: 12/23/2022] Open
Abstract
An involvement of components of DNA-break repair (DBR) complex including DNA-dependent protein kinase (DNA-PK) and poly-ADP-ribose polymerase 1 (PARP-1) in transcription regulation in response to distinct cellular signalling has been revealed by different laboratories. Here, we explored the involvement of DNA-PK and PARP-1 in the heat shock induced transcription of Hsp70A1A. We find that inhibition of both the catalytic subunit of DNA-PK (DNA-PKc), and Ku70, a regulatory subunit of DNA-PK holo-enzyme compromises transcription of Hsp70A1A under heat shock treatment. In immunoprecipitation based experiments we find that Ku70 or DNA-PK holoenzyme associates with NFκB. This NFκB associated complex also carries PARP-1. Downregulation of both NFκB and PARP-1 compromises Hsp70A1A transcription induced by heat shock treatment. Alteration of three bases by site directed mutagenesis within the consensus κB sequence motif identified on the promoter affected inducibility of Hsp70A1A transcription by heat shock treatment. These results suggest that NFκB engaged with the κB motif on the promoter cooperates in Hsp70A1A activation under heat shock in human cells as part of a DBR complex including DNA-PK and PARP-1.
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Affiliation(s)
- Joyita Hazra
- Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata, India
| | - Pooja Mukherjee
- Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata, India
| | - Asif Ali
- Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata, India
| | - Soumita Poddar
- Bioinformatics Center, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata, India
| | - Mahadeb Pal
- Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata, India
- * E-mail:
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5
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Pastukh VM, Gorodnya OM, Gillespie MN, Ruchko MV. Regulation of mitochondrial genome replication by hypoxia: The role of DNA oxidation in D-loop region. Free Radic Biol Med 2016; 96:78-88. [PMID: 27091693 PMCID: PMC4912408 DOI: 10.1016/j.freeradbiomed.2016.04.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 03/18/2016] [Accepted: 04/14/2016] [Indexed: 02/04/2023]
Abstract
Mitochondria of mammalian cells contain multiple copies of mitochondrial (mt) DNA. Although mtDNA copy number can fluctuate dramatically depending on physiological and pathophysiologic conditions, the mechanisms regulating mitochondrial genome replication remain obscure. Hypoxia, like many other physiologic stimuli that promote growth, cell proliferation and mitochondrial biogenesis, uses reactive oxygen species as signaling molecules. Emerging evidence suggests that hypoxia-induced transcription of nuclear genes requires controlled DNA damage and repair in specific sequences in the promoter regions. Whether similar mechanisms are operative in mitochondria is unknown. Here we test the hypothesis that controlled oxidative DNA damage and repair in the D-loop region of the mitochondrial genome are required for mitochondrial DNA replication and transcription in hypoxia. We found that hypoxia had little impact on expression of mitochondrial proteins in pulmonary artery endothelial cells, but elevated mtDNA content. The increase in mtDNA copy number was accompanied by oxidative modifications in the D-loop region of the mitochondrial genome. To investigate the role of this sequence-specific oxidation of mitochondrial genome in mtDNA replication, we overexpressed mitochondria-targeted 8-oxoguanine glycosylase Ogg1 in rat pulmonary artery endothelial cells, enhancing the mtDNA repair capacity of transfected cells. Overexpression of Ogg1 resulted in suppression of hypoxia-induced mtDNA oxidation in the D-loop region and attenuation of hypoxia-induced mtDNA replication. Ogg1 overexpression also reduced binding of mitochondrial transcription factor A (TFAM) to both regulatory and coding regions of the mitochondrial genome without altering total abundance of TFAM in either control or hypoxic cells. These observations suggest that oxidative DNA modifications in the D-loop region during hypoxia are important for increased TFAM binding and ensuing replication of the mitochondrial genome.
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Affiliation(s)
- Viktor M Pastukh
- Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
| | - Olena M Gorodnya
- Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
| | - Mark N Gillespie
- Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
| | - Mykhaylo V Ruchko
- Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
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Scovell WM. High mobility group protein 1: A collaborator in nucleosome dynamics and estrogen-responsive gene expression. World J Biol Chem 2016; 7:206-222. [PMID: 27247709 PMCID: PMC4877529 DOI: 10.4331/wjbc.v7.i2.206] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 02/19/2016] [Accepted: 03/14/2016] [Indexed: 02/05/2023] Open
Abstract
High mobility group protein 1 (HMGB1) is a multifunctional protein that interacts with DNA and chromatin to influence the regulation of transcription, DNA replication and repair and recombination. We show that HMGB1 alters the structure and stability of the canonical nucleosome (N) in a nonenzymatic, adenosine triphosphate-independent manner. As a result, the canonical nucleosome is converted to two stable, physically distinct nucleosome conformers. Although estrogen receptor (ER) does not bind to its consensus estrogen response element within a nucleosome, HMGB1 restructures the nucleosome to facilitate strong ER binding. The isolated HMGB1-restructured nucleosomes (N’ and N’’) remain stable and exhibit a number of characteristics that are distinctly different from the canonical nucleosome. These findings complement previous studies that showed (1) HMGB1 stimulates in vivo transcriptional activation at estrogen response elements and (2) knock down of HMGB1 expression by siRNA precipitously reduced transcriptional activation. The findings indicate that a major facet of the mechanism of HMGB1 action involves a restructuring of aspects of the nucleosome that appear to relax structural constraints within the nucleosome. The findings are extended to reveal the differences between ER and the other steroid hormone receptors. A working proposal outlines mechanisms that highlight the multiple facets that HMGB1 may utilize in restructuring the nucleosome.
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7
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Wang Y, Viscarra J, Kim SJ, Sul HS. Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol 2016; 16:678-89. [PMID: 26490400 DOI: 10.1038/nrm4074] [Citation(s) in RCA: 500] [Impact Index Per Article: 55.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy distribution to other tissues. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcriptional level. Transcription factors, such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles in this process. Recently, insights have been gained into the signalling pathways that regulate these transcription factors. After feeding, high blood glucose and insulin levels activate lipogenic genes through several pathways, including the DNA-dependent protein kinase (DNA-PK), atypical protein kinase C (aPKC) and AKT-mTOR pathways. These pathways control the post-translational modifications of transcription factors and co-regulators, such as phosphorylation, acetylation or ubiquitylation, that affect their function, stability and/or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance.
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Affiliation(s)
- Yuhui Wang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720, USA
| | - Jose Viscarra
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720, USA
| | - Sun-Joong Kim
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720, USA
| | - Hei Sook Sul
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720, USA
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8
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Bunch H. Role of genome guardian proteins in transcriptional elongation. FEBS Lett 2016; 590:1064-75. [PMID: 27010360 DOI: 10.1002/1873-3468.12152] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 03/18/2016] [Accepted: 03/21/2016] [Indexed: 12/17/2022]
Abstract
Maintaining genomic integrity is vital for cell survival and homeostasis. Mutations in critical genes in germ-line and somatic cells are often implicated with the onset or progression of diseases. DNA repair enzymes thus take important roles as guardians of the genome in the cell. Besides the known function to repair DNA damage, recent findings indicate that DNA repair enzymes regulate the transcription of protein-coding and noncoding RNA genes. In particular, a novel role of DNA damage response signaling has been identified in the regulation of transcriptional elongation. Topoisomerases-mediated DNA breaks appear important for the regulation. In this review, recent findings of these DNA break- and repair-associated enzymes in transcription and potential roles of transcriptional activation-coupled DNA breaks are discussed.
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Affiliation(s)
- Heeyoun Bunch
- Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA
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9
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Bunch H, Lawney BP, Lin YF, Asaithamby A, Murshid A, Wang YE, Chen BPC, Calderwood SK. Transcriptional elongation requires DNA break-induced signalling. Nat Commun 2015; 6:10191. [PMID: 26671524 PMCID: PMC4703865 DOI: 10.1038/ncomms10191] [Citation(s) in RCA: 159] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 11/13/2015] [Indexed: 01/20/2023] Open
Abstract
We have previously shown that RNA polymerase II (Pol II) pause release and transcriptional elongation involve phosphorylation of the factor TRIM28 by the DNA damage response (DDR) kinases ATM and DNA-PK. Here we report a significant role for DNA breaks and DDR signalling in the mechanisms of transcriptional elongation in stimulus-inducible genes in humans. Our data show the enrichment of TRIM28 and γH2AX on serum-induced genes and the important function of DNA-PK for Pol II pause release and transcriptional activation-coupled DDR signalling on these genes. γH2AX accumulation decreases when P-TEFb is inhibited, confirming that DDR signalling results from transcriptional elongation. In addition, transcriptional elongation-coupled DDR signalling involves topoisomerase II because inhibiting this enzyme interferes with Pol II pause release and γH2AX accumulation. Our findings propose that DDR signalling is required for effective Pol II pause release and transcriptional elongation through a novel mechanism involving TRIM28, DNA-PK and topoisomerase II. RNA polymerase II (Pol II) pause release and transcriptional elongation involve phosphorylation of TRIM28 by the DNA damage response (DDR) kinases. Here, Bunch et al. show that DDR signalling is coupled with and required for transcriptional elongation in stimulus-inducible genes and involves topoisomerase II.
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Affiliation(s)
- Heeyoun Bunch
- Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Brian P Lawney
- Center for Cancer Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02130, USA
| | - Yu-Fen Lin
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Aroumougame Asaithamby
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Ayesha Murshid
- Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Yaoyu E Wang
- Center for Cancer Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02130, USA
| | - Benjamin P C Chen
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Stuart K Calderwood
- Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA
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Dekker SL, Kampinga HH, Bergink S. DNAJs: more than substrate delivery to HSPA. Front Mol Biosci 2015; 2:35. [PMID: 26176011 PMCID: PMC4485348 DOI: 10.3389/fmolb.2015.00035] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 06/12/2015] [Indexed: 11/20/2022] Open
Abstract
Proteins are essential components of cellular life, as building blocks, but also to guide and execute all cellular processes. Proteins require a three-dimensional folding, which is constantly being challenged by their environment. Challenges including elevated temperatures or redox changes can alter this fold and result in misfolding of proteins or even aggregation. Cells are equipped with several pathways that can deal with protein stress. Together, these pathways are referred to as the protein quality control network. The network comprises degradation and (re)folding pathways that are intertwined due to the sharing of components and by the overlap in affinity for substrates. Here, we will give examples of this sharing and intertwinement of protein degradation and protein folding and discuss how the fate of a substrate is determined. We will focus on the ubiquitylation of substrates and the role of Hsp70 co-chaperones of the DNAJ class in this process.
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Affiliation(s)
- Suzanne L Dekker
- Department of Cell Biology, University Medical Center Groningen, University of Groningen Groningen, Netherlands
| | - Harm H Kampinga
- Department of Cell Biology, University Medical Center Groningen, University of Groningen Groningen, Netherlands
| | - Steven Bergink
- Department of Cell Biology, University Medical Center Groningen, University of Groningen Groningen, Netherlands
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11
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Ketron AC, Osheroff N. Phytochemicals as Anticancer and Chemopreventive Topoisomerase II Poisons. PHYTOCHEMISTRY REVIEWS : PROCEEDINGS OF THE PHYTOCHEMICAL SOCIETY OF EUROPE 2014; 13:19-35. [PMID: 24678287 PMCID: PMC3963363 DOI: 10.1007/s11101-013-9291-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Phytochemicals are a rich source of anticancer drugs and chemopreventive agents. Several of these chemicals appear to exert at least some of their effects through interactions with topoisomerase II, an essential enzyme that regulates DNA supercoiling and removes knots and tangles from the genome. Topoisomerase II-active phytochemicals function by stabilizing covalent protein-cleaved DNA complexes that are intermediates in the catalytic cycle of the enzyme. As a result, these compounds convert topoisomerase II to a cellular toxin that fragments the genome. Because of their mode of action, they are referred to as topoisomerase II poisons as opposed to catalytic inhibitors. The first sections of this article discuss DNA topology, the catalytic cycle of topoisomerase II, and the two mechanisms (interfacial vs. covalent) by which different classes of topoisomerase II poisons alter enzyme activity. Subsequent sections discuss the effects of several phytochemicals on the type II enzyme, including demethyl-epipodophyllotoxins (semisynthetic anticancer drugs) as well as flavones, flavonols, isoflavones, catechins, isothiocyanates, and curcumin (dietary chemopreventive agents). Finally, the leukemogenic potential of topoisomerase II-targeted phytochemicals is described.
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Affiliation(s)
- Adam C. Ketron
- Department of Biochemistry and the Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 USA
| | - Neil Osheroff
- Departments of Biochemistry and Medicine (Hematology/Oncology) and the Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 USA
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12
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Isabelle M, Gallouzi IE, Poirier GG. PARP1 parylation promotes silent locus transmission in the nucleolus: the suspicion confirmed. Mol Cell 2012; 45:706-7. [PMID: 22464439 DOI: 10.1016/j.molcel.2012.03.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Parylation modulates various processes, including transcription. In this issue of Molecular Cell, Guetg et al. (2012) show that, in the nucleolus, PARP1-mediated parylation of TIP5 promotes the silencing of rDNA chromatin during replication, uncovering the mechanism by which PARP1 ensures that silent rDNA regions are properly inherited.
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Affiliation(s)
- Maxim Isabelle
- Centre de recherche du CHUQ-Pavillon CHUL, Cancer Axis, Québec, Canada
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13
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Gillespie MN, Pastukh VM, Ruchko MV. Controlled DNA "damage" and repair in hypoxic signaling. Respir Physiol Neurobiol 2010; 174:244-51. [PMID: 20831905 PMCID: PMC3031145 DOI: 10.1016/j.resp.2010.08.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2010] [Accepted: 08/31/2010] [Indexed: 12/29/2022]
Abstract
Hypoxia, a fundamental stimulus in biology and medicine, uses reactive oxygen species (ROS) as second messengers. A surprising target of hypoxia-generated ROS is specific bases within hypoxic response elements (HREs) of the VEGF and other hypoxia-inducible genes. Oxidative modifications coincide with the onset of mRNA accumulation and are localized to transcriptionally active mono-nucleosomes. The oxidative base modifications are removed by the base excision DNA repair pathway for which one of its components, the bifunctional transcriptional co-activator and DNA endonuclease Ref-1/Ape1, is critical for transcription complex assembly. Mimicking the effect of hypoxia by introducing an abasic site in an oligonucleotide model of the VEGF HRE, altered transcription factor binding, enhanced sequence flexibility, and engendered more robust reporter gene expression. These observations suggest that controlled DNA "damage" and repair, mediated by ROS used as second messengers and critically involving the base excision pathway of DNA repair, respectively, are important for hypoxia-induced transcriptional activation.
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Affiliation(s)
- Mark N Gillespie
- Department of Pharmacology and Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688-0002, United States.
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14
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Abstract
Type II topoisomerases are essential enzymes that regulate DNA under- and overwinding and remove knots and tangles from the genetic material. In order to carry out their critical physiological functions, these enzymes utilize a double-stranded DNA passage mechanism that requires them to generate a transient double-stranded break. Consequently, while necessary for cell survival, type II topoisomerases also have the capacity to fragment the genome. This feature of the prokaryotic and eukaryotic enzymes, respectively, is exploited to treat a variety of bacterial infections and cancers in humans. All type II topoisomerases require divalent metal ions for catalytic function. These metal ions function in two separate active sites and are necessary for the ATPase and DNA cleavage/ligation activities of the enzymes. ATPase activity is required for the strand passage process and utilizes the metal-dependent binding and hydrolysis of ATP to drive structural rearrangements in the protein. Both the DNA cleavage and ligation activities of type II topoisomerases require divalent metal ions and appear to utilize a novel variant of the canonical two-metal-ion phosphotransferase/hydrolase mechanism to facilitate these reactions. This article will focus primarily on eukaryotic type II topoisomerases and the roles of metal ions in the catalytic functions of these enzymes.
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Affiliation(s)
- Joseph E. Deweese
- Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204-3951
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 USA
| | - Neil Osheroff
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 USA
- Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 USA
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15
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Abstract
Hypoxia, a fundamental biological stimulus, uses reactive oxygen species (ROS) as second messengers. Surprising molecular targets of hypoxia-generated ROS are the specific bases within hypoxic response elements (HREs) of the vascular endothelial growth factor (VEGF) and other hypoxia-inducible genes. Oxidative modifications coincide with the onset of mRNA accumulation and are localized to transcriptionally active mononucleosomes. The oxidative base modifications are removed, and the base excision DNA repair pathway is likely involved since Ref-1/Ape1, a transcriptional co-activator and DNA repair enzyme, is critical for transcription complex assembly. Mimicking the effect of hypoxia by introducing an abasic site in an oligonucleotide-based model of ROS-enhanced VEGF HRE sequence flexibility resulted in altered transcription factor binding and engendered more robust reporter gene expression. These observations suggest that controlled DNA "damage" and repair, mediated by ROS used as second messengers and by the base excision pathway of DNA repair, respectively, are important for hypoxia-induced transcriptional activation.
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Affiliation(s)
- Mark N Gillespie
- Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL 36688-0002, USA.
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16
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Park E, Griffin DE. Interaction of Sindbis virus non-structural protein 3 with poly(ADP-ribose) polymerase 1 in neuronal cells. J Gen Virol 2009; 90:2073-80. [PMID: 19515826 DOI: 10.1099/vir.0.012682-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The alphavirus non-structural protein 3 (nsP3) has a conserved N-terminal macro domain and a variable highly phosphorylated C-terminal domain. nsP3 forms complexes with cellular proteins, but its role in virus replication is poorly understood and protein interaction domains have not been defined. As the N-terminal macro domain can bind poly(ADP-ribose) (PAR), and PAR polymerase-1 (PARP-1) is activated and autoribosylated during Sindbis virus (SINV) infection, it was hypothesized that PARP-1 and nsP3 may interact. Co-immunoprecipitation studies showed that PARP-1 interacted with nsP3 during SINV infection of NSC34 neuronal cells and was most abundantly present in replication complexes that contained plus- and minus-strand SINV RNAs 10-14 h after infection, prior to PARP-1 activation or automodification with PAR. Treatment with an inhibitor of PARP enzymic activity did not affect the interaction between nsP3 and PARP-1 or SINV replication. Co-expression of individual domains of nsP3 with PARP-1 showed that nsP3 interacted with PARP-1 through the C-terminal domain, not the N-terminal macro domain, and that phosphorylation was not required. It was concluded that PARP-1 interacts with the C-terminal domain of nsP3, is present in replication complexes during virus amplification and may play a role in regulating virus RNA synthesis in neuronal cells.
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Affiliation(s)
- Eunhye Park
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health and Cellular and Molecular Medicine Graduate Program, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
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Ruchko MV, Gorodnya OM, Pastukh VM, Swiger BM, Middleton NS, Wilson GL, Gillespie MN. Hypoxia-induced oxidative base modifications in the VEGF hypoxia-response element are associated with transcriptionally active nucleosomes. Free Radic Biol Med 2009; 46:352-9. [PMID: 18992807 PMCID: PMC2645035 DOI: 10.1016/j.freeradbiomed.2008.09.038] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2008] [Revised: 09/18/2008] [Accepted: 09/29/2008] [Indexed: 11/19/2022]
Abstract
Reactive oxygen species (ROS) generated in hypoxic pulmonary artery endothelial cells cause transient oxidative base modifications in the hypoxia-response element (HRE) of the VEGF gene that bear a conspicuous relationship to induction of VEGF mRNA expression (K.A. Ziel et al., FASEB J. 19, 387-394, 2005). If such base modifications are indeed linked to transcriptional regulation, then they should be detected in HRE sequences associated with transcriptionally active nucleosomes. Southern blot analysis of the VEGF HRE associated with nucleosome fractions prepared by micrococcal nuclease digestion indicated that hypoxia redistributed some HRE sequences from multinucleosomes to transcriptionally active mono- and dinucleosome fractions. A simple PCR method revealed that VEGF HRE sequences harboring oxidative base modifications were found exclusively in mononucleosomes. Inhibition of hypoxia-induced ROS generation with myxathiozol prevented formation of oxidative base modifications but not the redistribution of HRE sequences into mono- and dinucleosome fractions. The histone deacetylase inhibitor trichostatin A caused retention of HRE sequences in compacted nucleosome fractions and prevented formation of oxidative base modifications. These findings suggest that the hypoxia-induced oxidant stress directed at the VEGF HRE requires the sequence to be repositioned into mononucleosomes and support the prospect that oxidative modifications in this sequence are an important step in transcriptional activation.
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Affiliation(s)
- Mykhaylo V Ruchko
- Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA
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18
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Deweese JE, Osheroff N. The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothing. Nucleic Acids Res 2008; 37:738-48. [PMID: 19042970 PMCID: PMC2647315 DOI: 10.1093/nar/gkn937] [Citation(s) in RCA: 351] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Topoisomerase II is an essential enzyme that is required for virtually every process that requires movement of DNA within the nucleus or the opening of the double helix. This enzyme helps to regulate DNA under- and overwinding and removes knots and tangles from the genetic material. In order to carry out its critical physiological functions, topoisomerase II generates transient double-stranded breaks in DNA. Consequently, while necessary for cell survival, the enzyme also has the capacity to fragment the genome. The DNA cleavage/ligation reaction of topoisomerase II is the target for some of the most successful anticancer drugs currently in clinical use. However, this same reaction also is believed to trigger chromosomal translocations that are associated with specific types of leukemia. This article will familiarize the reader with the DNA cleavage/ligation reaction of topoisomerase II and other aspects of its catalytic cycle. In addition, it will discuss the interaction of the enzyme with anticancer drugs and the mechanisms by which these agents increase levels of topoisomerase II-generated DNA strand breaks. Finally, it will describe dietary and environmental agents that enhance DNA cleavage mediated by the enzyme.
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Affiliation(s)
- Joseph E Deweese
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146 USA
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19
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Cohausz O, Althaus FR. Role of PARP-1 and PARP-2 in the expression of apoptosis-regulating genes in HeLa cells. Cell Biol Toxicol 2008; 25:379-91. [DOI: 10.1007/s10565-008-9092-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2008] [Accepted: 05/30/2008] [Indexed: 11/24/2022]
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Pastukh V, Ruchko M, Gorodnya O, Wilson GL, Gillespie MN. Sequence-specific oxidative base modifications in hypoxia-inducible genes. Free Radic Biol Med 2007; 43:1616-26. [PMID: 18037127 DOI: 10.1016/j.freeradbiomed.2007.08.027] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Revised: 08/23/2007] [Accepted: 08/24/2007] [Indexed: 11/28/2022]
Abstract
Reactive oxygen species associated with hypoxic signaling in pulmonary arterial endothelial cells (PAECs) oxidatively modify specific nucleotides in the hypoxic response element (HRE) of the VEGF gene (FASEB J.19:387-394; 2005). In this study, we determined in PAECs if hypoxia caused genome-wide oxidative modifications or if they were restricted to the promoters of genes differentially regulated by hypoxia. Comet assays indicated that there were no differences between normoxic and hypoxic PAECs in terms of global DNA damage. However, a simple PCR-based method involving DNA amplification before and after treatment with formamidopyrimidine DNA glycosylase (Fpg), a bacterial DNA repair enzyme that cleaves at sites of purine base oxidation, revealed that hypoxia caused modifications in the HREs of the hypoxia-inducible VEGF, HO-1, and ET-1 genes which coincided with accumulation of their respective mRNA transcripts. Promoter sequences not involved with hypoxic induction and coding regions of these genes failed to display Fpg-sensitive sites. Oxidative modifications also were not detected in sequences of the hypoxia down-regulated ornithine decarboxylase and TFAM genes or the constitutively expressed beta-actin gene. These findings show that hypoxia-mediated oxidative DNA modifications cluster in functionally relevant promoter sequences in hypoxia-inducible genes and suggest that such oxidative modifications may be biologically significant.
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Affiliation(s)
- Viktor Pastukh
- Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA
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21
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Alvarez-Gonzalez R. Genomic maintenance: the p53 poly(ADP-ribosyl)ation connection. ACTA ACUST UNITED AC 2007; 2007:pe68. [PMID: 18056913 DOI: 10.1126/stke.4152007pe68] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The integrity of the genome in higher eukaryotes, as well as the modulation of its complex structure and functions, is exquisitely regulated. This genomic regulation occurs as a function of time in a very sophisticated and elaborate biological process called cell cycle progression, resulting in cell division, and is also controlled by a highly coordinated and intricate network of molecular signaling pathways, which in turn orchestrate very specific macromolecular interactions among nuclear proteins and DNA at the biochemical level. Among the latter, a prominent enzymatic cycle that is involved in maintaining the integrity of mammalian chromosomes is covalent protein-poly[adenosine diphosphate (ADP)-ribosyl]ation. The importance of this posttranslational modification is illustrated by the close cooperation between two "guardian angels" of the genome, one constitutive and one inducible protein, namely poly(ADP-ribose) polymerase-1 (PARP-1) and p53, and the integration of these pivotal signaling processes with genomic maintenance.
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Affiliation(s)
- Rafael Alvarez-Gonzalez
- Department of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA.
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22
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Zaniolo K, Desnoyers S, Leclerc S, Guérin SL. Regulation of poly(ADP-ribose) polymerase-1 (PARP-1) gene expression through the post-translational modification of Sp1: a nuclear target protein of PARP-1. BMC Mol Biol 2007; 8:96. [PMID: 17961220 PMCID: PMC2175517 DOI: 10.1186/1471-2199-8-96] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2007] [Accepted: 10/25/2007] [Indexed: 01/09/2023] Open
Abstract
Background Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that plays critical functions in many biological processes, including DNA repair and gene transcription. The main function of PARP-1 is to catalyze the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to a large array of acceptor proteins, which comprises histones, transcription factors, as well as PARP-1 itself. We have previously demonstrated that transcription of the PARP-1 gene essentially rely on the opposite regulatory actions of two distinct transcription factors, Sp1 and NFI. In the present study, we examined whether suppression of PARP-1 expression in embryonic fibroblasts derived from PARP-1 knockout mice (PARP-1-/-) might alter the expression and/or DNA binding properties of Sp1 and NFI. We also explored the possibility that Sp1 or NFI (or both) may represent target proteins of PARP-1 activity. Results Expression of both Sp1 and NFI was found to be considerably reduced in PARP-1-/- cells. Co-immunoprecipitation assays revealed that PARP-1 physically interacts with Sp1 in a DNA-independent manner, but neither with Sp3 nor NFI, in PARP-1+/+ cells. In addition, in vitro PARP assays indicated that PARP-1 could catalyze the addition of polymer of ADP-ribose to Sp1, which also translated into a reduction of Sp1 binding to its consensus DNA target site. Transfection of the PARP-1 promoter into both PARP-1+/+ and PARP-1-/- cells revealed that the lack of PARP-1 expression in PARP-1-/- cells also results in a strong increase in PARP-1 promoter activity. This influence of PARP-1 was found to rely on the presence of the Sp1 sites present on the basal PARP-1 promoter as their mutation entirely abolished the increased promoter activity observed in PARP-1-/- cells. Subjecting PARP-1+/+ cells to an oxidative challenge with hydrogen peroxide to increase PARP-1 activity translated into a dramatic reduction in the DNA binding properties of Sp1. However, its suppression by the inhibitor PJ34 improved DNA binding of Sp1 and led to a dramatic increase in PARP-1 promoter function. Conclusion Our results therefore recognized Sp1 as a target protein of PARP-1 activity, the addition of polymer of ADP-ribose to this transcription factor restricting its positive regulatory influence on gene transcription.
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Affiliation(s)
- Karine Zaniolo
- Oncology and Molecular Endocrinology Research Center, Centre de Recherche du CHUL-CHUQ and Département d'Anatomie-Physiologie, Université Laval, Québec, G1V 4G2, Canada.
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23
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Breit JF, Ault-Ziel K, Al-Mehdi AB, Gillespie MN. Nuclear protein‐induced bending and flexing of the hypoxic response element of the rat vascular endothelial growth factor promoter. FASEB J 2007; 22:19-29. [PMID: 17766324 DOI: 10.1096/fj.07-8102com] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Bending and flexing of DNA may contribute to transcriptional regulation. Because hypoxia and other physiological signals induce formation of an abasic site at a key base within the hypoxic response element (HRE) of the vascular endothelial growth factor (VEGF) gene (FASEB J. 19, 387-394, 2005) and because abasic sites can introduce flexibility in model DNA sequences, in the present study we used a fluorescence resonance energy transfer-based reporter system to assess topological changes in a wild-type (WT) sequence of the HRE of the rat VEGF gene and in a sequence harboring a single abasic site mimicking the effect of hypoxia. Binding of the hypoxia-inducible transcriptional complex present in hypoxic pulmonary artery endothelial cell nuclear extract to the WT sequence failed to alter sequence topology whereas nuclear protein binding to the modified HRE engendered considerable sequence flexibility. Topological effects of nuclear proteins on the modified VEGF HRE were dependent on the transcription factor hypoxia-inducible factor-1 and on formation of a single-strand break at the abasic site mediated by the coactivator, Ref-1/Ape1. These observations suggest that oxidative base modifications in the VEGF HRE evoked by physiological signals could be a precursor to single-strand break formation that has an impact on gene expression by modulating sequence flexibility.
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Affiliation(s)
- Jeffrey F Breit
- Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, Alabama 36688-0002, USA
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Ambrose HE, Papadopoulou V, Beswick RW, Wagner SD. Poly-(ADP-ribose) polymerase-1 (Parp-1) binds in a sequence-specific manner at the Bcl-6 locus and contributes to the regulation of Bcl-6 transcription. Oncogene 2007; 26:6244-52. [PMID: 17404575 DOI: 10.1038/sj.onc.1210434] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Bcl-6 is a transcription factor that is normally expressed in germinal centre B cells. It is essential for the formation of germinal centres and the production of high-affinity antibodies. Transcriptional downregulation of Bcl-6 occurs on terminal differentiation to plasma cells. Bcl-6 is highly expressed in B-cell non-Hodgkin's lymphoma and, in a subset of cases of diffuse large cell lymphoma, the mechanism of Bcl-6 overexpression involves interruption of normal transcriptional controls. Transcriptional control of Bcl-6 is, therefore, important for normal antibody responses and lymphomagenesis, but little is known of the cis-acting control elements. This report focuses on a region of mouse/human sequence homology in the first intron of Bcl-6, which is a candidate site for such a control element. We demonstrate that poly-(ADP-ribose) polymerase-1 (Parp-1) binds in vitro and in vivo to specific sequences in this region. We further show that PARP inhibitors, and Parp-1 knockdown by siRNA induce Bcl-6 mRNA expression in Bcl-6 expressing cell lines. We speculate that Parp-1 activation plays a role in switching off Bcl-6 transcription and subsequent B-cell exit from the germinal centre.
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Affiliation(s)
- H E Ambrose
- Division of Investigative Sciences, Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK
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