Transcription-Replication Collisions—A Series of Unfortunate Events
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Environmental Influences on Endothelial Gene Expression
ENDOTHELIAL CELL GENE EXPRESSION John Matthew Jeff Herbert Supervisors: Prof. Roy Bicknell and Dr. Victoria Heath PhD thesis University of Birmingham August 2012 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Tumour angiogenesis is a vital process in the pathology of tumour development and metastasis. Targeting markers of tumour endothelium provide a means of targeted destruction of a tumours oxygen and nutrient supply via destruction of tumour vasculature, which in turn ultimately leads to beneficial consequences to patients. Although current anti -angiogenic and vascular targeting strategies help patients, more potently in combination with chemo therapy, there is still a need for more tumour endothelial marker discoveries as current treatments have cardiovascular and other side effects. For the first time, the analyses of in-vivo biotinylation of an embryonic system is performed to obtain putative vascular targets. Also for the first time, deep sequencing is applied to freshly isolated tumour and normal endothelial cells from lung, colon and bladder tissues for the identification of pan-vascular-targets. Integration of the proteomic, deep sequencing, public cDNA libraries and microarrays, delivers 5,892 putative vascular targets to the science community. -
Holliday Junction Resolvases
Downloaded from http://cshperspectives.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Holliday Junction Resolvases Haley D.M. Wyatt and Stephen C. West London Research Institute, Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, United Kingdom Correspondence: [email protected] Four-way DNA intermediates, called Holliday junctions (HJs), can form during meiotic and mitotic recombination, and their removal is crucial for chromosome segregation. A group of ubiquitous and highly specialized structure-selective endonucleases catalyze the cleavage of HJs into two disconnected DNA duplexes in a reaction called HJ resolution. These enzymes, called HJ resolvases, have been identified in bacteria and their bacteriophages, archaea, and eukaryotes. In this review, we discuss fundamental aspects of the HJ structure and their interaction with junction-resolving enzymes. This is followed by a brief discussion of the eubacterial RuvABC enzymes, which provide the paradigm for HJ resolvases in other organisms. Finally, we review the biochemical and structural properties of some well-char- acterized resolvases from archaea, bacteriophage, and eukaryotes. omologous recombination (HR) is an es- homologous strand as a template for DNA syn- Hsential process that promotes genetic di- thesis. Recombination then proceeds in one of versity during meiosis (see Lam and Keeney several different ways, some of which involve 2014; Zickler and Kleckner 2014). However, in second-end capture, such that the other resect- somatic cells, HR plays a key role in conserv- ed 30 end anneals to the displaced strand of the ing genetic information by facilitating DNA re- D-loop (Szostak et al. -
NIH Public Access Author Manuscript Mol Cell
NIH Public Access Author Manuscript Mol Cell. Author manuscript; available in PMC 2011 November 2. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Mol Cell. 2002 December ; 10(6): 1503±1509. Drosophila mus312 encodes a novel protein that interacts physically with the nucleotide excision repair endonuclease MEI-9 to generate meiotic crossovers Özlem Yıldız1, Samarpan Majumder1, Benjamin Kramer1, and Jeff J. Sekelsky1,2,3 1Department of Biology University of North Carolina - Chapel Hill Chapel Hill, NC 27599 2Program in Molecular Biology and Biotechnology University of North Carolina - Chapel Hill Chapel Hill, NC 27599 Summary MEI-9 is the Drosophila homolog of the human structure-specific DNA endonuclease XPF. Like XPF, MEI-9 functions in nucleotide excision repair and interstrand crosslink repair. MEI-9 is also required to generate meiotic crossovers, in a function thought to be associated with resolution of Holliday junction intermediates. We report here the identification of MUS312, a novel protein that physically interacts with MEI-9. We show that mutations in mus312 elicit a meiotic phenotype identical to that of mei-9 mutants. A missense mutation in mei-9 that disrupts the MEI-9–MUS312 interaction abolishes the meiotic function of mei-9 but does not affect the DNA repair functions of mei-9. We propose that MUS312 facilitates resolution of meiotic Holliday junction intermediates by MEI-9. Introduction Genetic recombination is essential for the maintenance of genome stability. In meiosis, accurate segregation of homologous chromosomes depends on generation of crossovers by a homologous recombination pathway (reviewed in Kleckner, 1996; Roeder, 1997). -
Supplementary Materials
Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine -
Nucleoporin TPR Is an Integral Component of the TREX-2 Mrna Export Pathway
ARTICLE https://doi.org/10.1038/s41467-020-18266-2 OPEN Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway Vasilisa Aksenova1, Alexandra Smith1, Hangnoh Lee1, Prasanna Bhat 2, Caroline Esnault3, Shane Chen1, James Iben4, Ross Kaufhold1, Ka Chun Yau 1, Carlos Echeverria1, Beatriz Fontoura 2, Alexei Arnaoutov1 & ✉ Mary Dasso 1 Nuclear pore complexes (NPCs) are important for cellular functions beyond nucleocyto- 1234567890():,; plasmic trafficking, including genome organization and gene expression. This multi-faceted nature and the slow turnover of NPC components complicates investigations of how indi- vidual nucleoporins act in these diverse processes. To address this question, we apply an Auxin-Induced Degron (AID) system to distinguish roles of basket nucleoporins NUP153, NUP50 and TPR. Acute depletion of TPR causes rapid and pronounced changes in tran- scriptomic profiles. These changes are dissimilar to shifts observed after loss of NUP153 or NUP50, but closely related to changes caused by depletion of mRNA export receptor NXF1 or the GANP subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex. More- over, TPR depletion disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) to NPCs and results in abnormal RNA transcription and export. Our findings demonstrate a unique and pivotal role of TPR in gene expression through TREX-2- and/or NXF1-dependent mRNA turnover. 1 Division of Molecular and Cellular Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. 2 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 3 Bioinformatics and Scientific Programming Core, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20879, USA. -
SMX Makes the Cut in Genome Stability
www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 61), pp: 102765-102766 Editorial SMX makes the cut in genome stability Haley D.M. Wyatt and Stephen C. West The faithful duplication and preservation of our SLX4 scaffold co-ordinate three different nucleases for genetic material is essential for cell survival; however, DNA cleavage? SMX was found to be a promiscuous DNA is susceptible to damage by extracellular and endonuclease that cleaves a broad range of DNA secondary intracellular agents (e.g. ultraviolet radiation, reactive structures in vitro3. Remarkably, SLX4 co-ordinates the oxygen species). DNA double-strand breaks (DSBs) SLX1 and MUS81-EME1 nucleases during HJ resolution are thought to represent the most dangerous type of [3, 4] (Figure 1). The involvement of two active sites from lesion, as the failure to repair a DSB can lead to loss of different heterodimeric enzymes leads to a non-canonical genetic information, chromosomal rearrangements, and mechanism of HJ resolution. It was also shown that SLX4 cell death. Fortunately, cells contain sophisticated DNA activates MUS81-EME1 to cleave structures that resemble repair pathways to counteract the deleterious effects of stalled replication forks [3] (Figure 1). Activation involves genotoxic agents. Mutations in DNA repair genes are relaxation of MUS81-EME1’s substrate specificity, which linked to various diseases, including neurological defects, is regulated by a helix-hairpin-helix (HhH) domain in immunodeficiency, and cancer. the MUS81 N-terminus (MUS81 N-HhH). Intriguingly, Gross chromosomal rearrangements, including MUS81 N-HhH also mediates the interaction with deletions, duplications, and translocations, are a hallmark SLX4 via a C-terminal SAP domain (SLX4 SAP) [5]. -
Progression of Pathology in PINK1-Deficient Mouse Brain From
Torres-Odio et al. Journal of Neuroinflammation (2017) 14:154 DOI 10.1186/s12974-017-0928-0 RESEARCH Open Access Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation Sylvia Torres-Odio1†, Jana Key1†, Hans-Hermann Hoepken1, Júlia Canet-Pons1, Lucie Valek2, Bastian Roller3, Michael Walter4, Blas Morales-Gordo5, David Meierhofer6, Patrick N. Harter3, Michel Mittelbronn3,7,8,9,10, Irmgard Tegeder2, Suzana Gispert1 and Georg Auburger1* Abstract Background: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types. Methods: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts. Results: In a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”.Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3,andNfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. -
CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells
Author Manuscript Published OnlineFirst on March 11, 2020; DOI: 10.1158/0008-5472.CAN-19-1372 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Title: CHK1 inhibition is synthetically lethal with loss of B-family DNA polymerase function in human lung and colorectal cancer cells. Author List: Rebecca F. Rogers1, Mike I. Walton1, Daniel L. Cherry2, Ian Collins1, Paul A. Clarke1, Michelle D. Garrett2* and Paul Workman1* Affiliations: 1Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SM2 5NG, UK 2 School of Biosciences, Stacey Building, University of Kent, Canterbury, Kent, CT2 7NJ, UK Running title: Synthetic lethality of CHK1 and DNA polymerase inhibition *Corresponding authors: Michelle D Garrett and Paul Workman Corresponding Author Information Michelle D Garrett School of Biosciences, Stacey Building, University of Kent, Canterbury, Kent, CT2 7NJ, UK. Email: [email protected] Phone: +44 (0)1227 816140 Paul Workman Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SM2 5NG, UK. Email: [email protected] Phone: +44 (0)20 7153 5209 Conflict of interest statement: IC, MDG, MIW, RFR, PC and PW are current or past employees of The Institute of Cancer Research, which has a commercial interest in the discovery and development of CHK1 inhibitors, including SRA737, and operates a rewards-to- inventors scheme. IC, MDG and MIW have been involved in a commercial collaboration on CHK1 inhibitors with Sareum Ltd and intellectual property arising from the program, including SRA737, was licensed to Sierra Oncology. IC is a consultant for Sierra Oncology, Adorx Ltd, Epidarex LLP and Enterprise Therapeutics Ltd and holds equity in Monte Rosa Therapeutics AG. -
HHS Public Access Author Manuscript
HHS Public Access Author manuscript Author Manuscript Author ManuscriptGenet Epidemiol Author Manuscript. Author Author Manuscript manuscript; available in PMC 2016 June 01. Published in final edited form as: Genet Epidemiol. 2015 December ; 39(8): 664–677. doi:10.1002/gepi.21932. Multiple SNP-sets Analysis for Genome-wide Association Studies through Bayesian Latent Variable Selection Zhaohua Lu, Hongtu Zhu, Rebecca C Knickmeyer, Patrick F. Sullivan, Williams N. Stephanie, and Fei Zou for the Alzheimer’s Disease Neuroimaging Initiative* Departments of Biostatistics, Psychiatry, and Genetics and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Abstract The power of genome-wide association studies (GWAS) for mapping complex traits with single SNP analysis may be undermined by modest SNP effect sizes, unobserved causal SNPs, correlation among adjacent SNPs, and SNP-SNP interactions. Alternative approaches for testing the association between a single SNP-set and individual phenotypes have been shown to be promising for improving the power of GWAS. We propose a Bayesian latent variable selection (BLVS) method to simultaneously model the joint association mapping between a large number of SNP-sets and complex traits. Compared to single SNP-set analysis, such joint association mapping not only accounts for the correlation among SNP-sets, but also is capable of detecting causal SNP- sets that are marginally uncorrelated with traits. The spike-slab prior assigned to the effects of SNP-sets can greatly reduce the dimension of effective SNP-sets, while speeding up computation. An efficient MCMC algorithm is developed. Simulations demonstrate that BLVS outperforms several competing variable selection methods in some important scenarios. -
Expression of an Ortholog of Replication Protein A1 (RPA1)
Proc. Natl. Acad. Sci. USA Vol. 94, pp. 9979–9983, September 1997 Plant Biology Expression of an ortholog of replication protein A1 (RPA1) is induced by gibberellin in deepwater rice (cell divisionyintercalary meristemyinternodal growthyOryza sativa) ESTHER VAN DER KNAAP*, SANDRINE JAGOUEIX*†, AND HANS KENDE‡ Michigan State University–Department of Energy Plant Research Laboratory, Michigan State University, East Lansing, MI 48824-1312 Contributed by Hans Kende, July 16, 1997 ABSTRACT Internodes of deepwater rice are induced to antagonist of GA action in rice (6). Growth of the internode grow rapidly when plants become submerged. This adaptation is, ultimately, promoted by GA (5). enables deepwater rice to keep part of its foliage above the The primary target tissue of GA is the intercalary meristem rising flood waters during the monsoon season and to avoid of the internode, where GA enhances cell division activity and drowning. This growth response is, ultimately, elicited by the cell elongation (5, 7, 8). The intercalary meristem is a zone of plant hormone gibberellin (GA). The primary target tissue for about 3 mm in length and is located at the base of the internode GA action is the intercalary meristem of the internode. Using (9). Cells are displaced from the intercalary meristem into the differential display of mRNA, we have isolated a number of elongation zone, where they reach their final size. In GA- genes whose expression in the intercalary meristem is regu- treated internodes, the final cell length is about three to four lated by GA. The product of one of these genes was identified times longer than in control internodes (5, 7). -
Monitoring Replication Protein a (RPA) Dynamics in Homologous
Marquette University e-Publications@Marquette Biological Sciences Faculty Research and Biological Sciences, Department of Publications 9-19-2017 Monitoring Replication Protein A (RPA) Dynamics in Homologous Recombination Through Site-specific ncorI poration of Non- canonical Amino Acids Nilisha Pokhrel Marquette University Sofia Origanti Marquette University, [email protected] Eric Parker Davenport Marquette University Disha M. Gandhi Marquette University Kyle Kaniecki Columbia University See next page for additional authors Published version. Nucleic Acids Research, Vol. 45, No. 16 (September 19, 2017): 9413-9426. DOI. Authors Nilisha Pokhrel, Sofia Origanti, Eric Parker Davenport, Disha M. Gandhi, Kyle Kaniecki, Ryan A. Mehl, Eric C. Greene, Chris Dockendorff, and Edwin Antony This article is available at e-Publications@Marquette: https://epublications.marquette.edu/bio_fac/603 Published online 12 July 2017 Nucleic Acids Research, 2017, Vol. 45, No. 16 9413–9426 doi: 10.1093/nar/gkx598 Monitoring Replication Protein A (RPA) dynamics in homologous recombination through site-specific incorporation of non-canonical amino acids Nilisha Pokhrel1, Sofia Origanti1, Eric Parker Davenport1, Disha Gandhi2, Kyle Kaniecki3,4, Ryan A. Mehl5, Eric C. Greene3, Chris Dockendorff2 and Edwin Antony1,* 1Department of Biological Sciences, Marquette University, Milwaukee, WI 53201, USA, 2Department of Chemistry, Marquette University, Milwaukee, WI 53201, USA, 3Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY -
1 Structure-Specific Endonucleases Xpf and Mus81 Play Overlapping but Essential Roles in DNA Repair by Homologous Recombination
Author Manuscript Published OnlineFirst on April 10, 2013; DOI: 10.1158/0008-5472.CAN-12-3154 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Structure-specific endonucleases Xpf and Mus81 play overlapping but essential roles in DNA repair by homologous recombination Koji Kikuchi1*, Takeo Narita1*, Pham Thanh Van1, Junko Iijima1, Kouji Hirota1, Islam Shamima Keka1, Mohiuddin1, Katsuya Okawa2, Tetsuya Hori3, Tatsuo Fukagawa3, Jeroen Essers4, 5, Roland Kanaar5, Matthew C. Whitby6, Kaoru Sugasawa7, Yoshihito Taniguchi1, Katsumi Kitagawa8, and Shunichi Takeda1,† 1Department of Radiation Genetics, and 2Frontier Technology Center, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto 606-8501, Japan 3Department of Molecular Genetics, National Institute of Genetics and Sokendai, Mishima, Shizuoka 411-8540, Japan 4Department of Vascular Surgery, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands 5Department of Genetics and Department of Radiation Oncology, Cancer Genomics Center, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands 6Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK 7Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Hyogo 657-8501, Japan 8Center for Childhood Cancer, The Research Institute at Nationwide Children’s Hospital, 1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 10, 2013; DOI: 10.1158/0008-5472.CAN-12-3154 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 700 Children’s Drive, Columbus, Ohio 43205, USA Running title: Functional overlap between Xpf and Mus81 Keywords: homologous recombination, Xpf, Mus81, nuclease, chemotherapeutic agents.