Chromatin and Nucleosome Dynamics in DNA Damage and Repair
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The Functions of DNA Damage Factor RNF8 in the Pathogenesis And
Int. J. Biol. Sci. 2019, Vol. 15 909 Ivyspring International Publisher International Journal of Biological Sciences 2019; 15(5): 909-918. doi: 10.7150/ijbs.31972 Review The Functions of DNA Damage Factor RNF8 in the Pathogenesis and Progression of Cancer Tingting Zhou 1, Fei Yi 1, Zhuo Wang 1, Qiqiang Guo 1, Jingwei Liu 1, Ning Bai 1, Xiaoman Li 1, Xiang Dong 1, Ling Ren 2, Liu Cao 1, Xiaoyu Song 1 1. Institute of Translational Medicine, China Medical University; Key Laboratory of Medical Cell Biology, Ministry of Education; Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, China 2. Department of Anus and Intestine Surgery, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China Corresponding authors: Xiaoyu Song, e-mail: [email protected] and Liu Cao, e-mail: [email protected]. Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University; Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, 110122, China. Tel: +86 24 31939636, Fax: +86 24 31939636. © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2018.12.03; Accepted: 2019.02.08; Published: 2019.03.09 Abstract The really interesting new gene (RING) finger protein 8 (RNF8) is a central factor in DNA double strand break (DSB) signal transduction. -
Mediator of DNA Damage Checkpoint Protein 1 Facilitates V(D)J Recombination in Cells Lacking DNA Repair Factor XLF
biomolecules Article Mediator of DNA Damage Checkpoint Protein 1 Facilitates V(D)J Recombination in Cells Lacking DNA Repair Factor XLF Carole Beck 1,2, Sergio Castañeda-Zegarra 1,2 , Camilla Huse 1,2, Mengtan Xing 1,2 and Valentyn Oksenych 1,2,3,* 1 Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; [email protected] (C.B.); [email protected] (S.C.-Z.); [email protected] (C.H.); [email protected] (M.X.) 2 St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250 Sluppen, 7006 Trondheim, Norway 3 Department of Biosciences and Nutrition (BioNuT), Karolinska Institutet, 14183 Huddinge, Sweden * Correspondence: [email protected] Received: 27 November 2019; Accepted: 24 December 2019; Published: 30 December 2019 Abstract: DNA double-strand breaks (DSBs) trigger the Ataxia telangiectasia mutated (ATM)-dependent DNA damage response (DDR), which consists of histone H2AX, MDC1, RNF168, 53BP1, PTIP, RIF1, Rev7, and Shieldin. Early stages of B and T lymphocyte development are dependent on recombination activating gene (RAG)-induced DSBs that form the basis for further V(D)J recombination. Non-homologous end joining (NHEJ) pathway factors recognize, process, and ligate DSBs. Based on numerous loss-of-function studies, DDR factors were thought to be dispensable for the V(D)J recombination. In particular, mice lacking Mediator of DNA Damage Checkpoint Protein 1 (MDC1) possessed nearly wild-type levels of mature B and T lymphocytes in the spleen, thymus, and bone marrow. NHEJ factor XRCC4-like factor (XLF)/Cernunnos is functionally redundant with ATM, histone H2AX, and p53-binding protein 1 (53BP1) during the lymphocyte development in mice. -
Identification of Cyclophilin Gene Family in Soybean and Characterization of Gmcyp1
Western University Scholarship@Western Electronic Thesis and Dissertation Repository 7-4-2013 12:00 AM Identification of Cyclophilin gene family in soybean and characterization of GmCYP1 Hemanta Raj Mainali The University of Western Ontario Supervisor Dr. Sangeeta Dhaubhadel The University of Western Ontario Graduate Program in Biology A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Hemanta Raj Mainali 2013 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Agricultural Science Commons, Biochemistry Commons, Bioinformatics Commons, Biology Commons, Biotechnology Commons, Molecular Biology Commons, Plant Biology Commons, and the Plant Breeding and Genetics Commons Recommended Citation Mainali, Hemanta Raj, "Identification of Cyclophilin gene family in soybean and characterization of GmCYP1" (2013). Electronic Thesis and Dissertation Repository. 1362. https://ir.lib.uwo.ca/etd/1362 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Identification of Cyclophilin gene family in soybean and characterization of GmCYP1 (Thesis format: Monograph) by Hemanta Raj Mainali Graduate Program in Biology A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science The School of Graduate and Postdoctoral Studies The University of Western Ontario London, Ontario, Canada © Hemanta Raj Mainali 2013 Abstract I identified members of the Cyclophilin (CYP) gene family in soybean (Glycine max) and characterized the GmCYP1, one of the members of soybean CYP. -
Re-Coding the ‘Corrupt’ Code: CRISPR-Cas9 Interventions in Human Germ Line Editing
Re-coding the ‘corrupt’ code: CRISPR-Cas9 interventions in human germ line editing CRISPR-Cas9, Germline Intervention, Human Cognition, Human Rights, International Regulation Master Thesis Tilburg University- Law and Technology 2018-19 Tilburg Institute for Law, Technology, and Society (TILT) October 2019 Student: Srishti Tripathy Supervisors: Prof. Dr. Robin Pierce SRN: 2012391 Dr. Emre Bayamlioglu ANR: 659785 Re-coding the ‘corrupt’ code CRISPR-Cas9, Germline Intervention, Human Cognition, Human Rights, International Regulation This page is intentionally left blank 2 Re-coding the ‘corrupt’ code CRISPR-Cas9, Germline Intervention, Human Cognition, Human Rights, International Regulation 3 Re-coding the ‘corrupt’ code CRISPR-Cas9, Germline Intervention, Human Cognition, Human Rights, International Regulation Table of Contents CHAPTER 1: Introduction .............................................................................................................. 6 1.1 Introduction and Review - “I think I’m crazy enough to do it” ......................................................................... 6 1.2 Research Question and Sub Questions .......................................................................................................................... 9 1.4 Methodology ............................................................................................................................................................................. 9 1.4 Thesis structure: ................................................................................................................................................................. -
Further Insights Into the Regulation of the Fanconi Anemia FANCD2 Protein
University of Rhode Island DigitalCommons@URI Open Access Dissertations 2015 Further Insights Into the Regulation of the Fanconi Anemia FANCD2 Protein Rebecca Anne Boisvert University of Rhode Island, [email protected] Follow this and additional works at: https://digitalcommons.uri.edu/oa_diss Recommended Citation Boisvert, Rebecca Anne, "Further Insights Into the Regulation of the Fanconi Anemia FANCD2 Protein" (2015). Open Access Dissertations. Paper 397. https://digitalcommons.uri.edu/oa_diss/397 This Dissertation is brought to you for free and open access by DigitalCommons@URI. It has been accepted for inclusion in Open Access Dissertations by an authorized administrator of DigitalCommons@URI. For more information, please contact [email protected]. FURTHER INSIGHTS INTO THE REGULATION OF THE FANCONI ANEMIA FANCD2 PROTEIN BY REBECCA ANNE BOISVERT A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CELL AND MOLECULAR BIOLOGY UNIVERSITY OF RHODE ISLAND 2015 DOCTOR OF PHILOSOPHY DISSERTATION OF REBECCA ANNE BOISVERT APPROVED: Dissertation Committee: Major Professor Niall Howlett Paul Cohen Becky Sartini Nasser H. Zawia DEAN OF THE GRADUATE SCHOOL UNIVERSITY OF RHODE ISLAND 2015 ABSTRACT Fanconi anemia (FA) is a rare autosomal and X-linked recessive disorder, characterized by congenital abnormalities, pediatric bone marrow failure and cancer susceptibility. FA is caused by biallelic mutations in any one of 16 genes. The FA proteins function cooperatively in the FA-BRCA pathway to repair DNA interstrand crosslinks (ICLs). The monoubiquitination of FANCD2 and FANCI is a central step in the activation of the FA-BRCA pathway and is required for targeting these proteins to chromatin. -
Polo-Like Kinase 1 in Genomic Instability
Polo-like Kinase 1 in genomic instability Xiaoqi Liu Department of Toxicology and Cancer Biology University of Kentucky The fate of a single parental chromosome throughout the eukaryotic cell cycle Cytokinesis Activation of cell division Preparation for mitosis The stages of mitosis and cytokinesis in an animal cell MT MT - + kinetochore Centrosome Spindle pole + (MTOC) Spindle pole Centrosome Spindle Nucleus G2 Prophase Prometaphase Metaphase Central spindle Contractile ring Midbody Anaphase Telophase Cytokinesis Control of mitotic entry and exit by Cdc2/cyclin B and APC Anaphase promoting complex (APC) Cdc2 Cyclin B Cdc2 Anaphase inhibitor Cyclin B Cdc2 G2 Prophase Metaphase Anaphase Telophase G1 (Liu & Erikson, PNAS 2002; Liu & Erikson, PNAS 2003; Liu et al, MCB 2005; Liu et al, MCB 2006) The polo-like kinases have a C-terminal polo-box domain M-phase kinase domain polo-box Plk1 603 Plx1 (Xl) 80% 598 polo (Dm) 65% 576 Plo1 (Sp) 50% 683 Cdc5 (Sc) 51% 705 Early phase of cell cycle Plk2 52% 683 Plk3 52% 631 Plk1 localizes to mitotic structures G2/pro Prometa Spindle poles Centrosomes kinetochores Centrosomes Centrosomes kinetochores Meta Telo Spindle poles Midbodies kinetochores Spindle poles Central spindles kinetochores Plk1 in cancer ---Plk1 overexpression is correlated with cell proliferation and carcinogenesis. ---Plk1 is a new diagnostic marker for cancer. ---Plk1 inhibitors are in various clinical trails. ---However, how Plk1 contributes to carcinogenesis is elusive. Does Plk1 elevation contribute to cancer progression? Approach: -
Insights Into Regulation of Human RAD51 Nucleoprotein Filament Activity During
Insights into Regulation of Human RAD51 Nucleoprotein Filament Activity During Homologous Recombination Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ravindra Bandara Amunugama, B.S. Biophysics Graduate Program The Ohio State University 2011 Dissertation Committee: Richard Fishel PhD, Advisor Jeffrey Parvin MD PhD Charles Bell PhD Michael Poirier PhD Copyright by Ravindra Bandara Amunugama 2011 ABSTRACT Homologous recombination (HR) is a mechanistically conserved pathway that occurs during meiosis and following the formation of DNA double strand breaks (DSBs) induced by exogenous stresses such as ionization radiation. HR is also involved in restoring replication when replication forks have stalled or collapsed. Defective recombination machinery leads to chromosomal instability and predisposition to tumorigenesis. However, unregulated HR repair system also leads to similar outcomes. Fortunately, eukaryotes have evolved elegant HR repair machinery with multiple mediators and regulatory inputs that largely ensures an appropriate outcome. A fundamental step in HR is the homology search and strand exchange catalyzed by the RAD51 recombinase. This process requires the formation of a nucleoprotein filament (NPF) on single-strand DNA (ssDNA). In Chapter 2 of this dissertation I describe work on identification of two residues of human RAD51 (HsRAD51) subunit interface, F129 in the Walker A box and H294 of the L2 ssDNA binding region that are essential residues for salt-induced recombinase activity. Mutation of F129 or H294 leads to loss or reduced DNA induced ATPase activity and formation of a non-functional NPF that eliminates recombinase activity. DNA binding studies indicate that these residues may be essential for sensing the ATP nucleotide for a functional NPF formation. -
RNF168 Ubiquitylates 53BP1 and Controls Its Response to DNA Double-Strand Breaks
RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks Miyuki Bohgakia,b,1, Toshiyuki Bohgakia,b,1, Samah El Ghamrasnia,b, Tharan Srikumara,b, Georges Mairec, Stephanie Panierd, Amélie Fradet-Turcotted, Grant S. Stewarte, Brian Raughta,b, Anne Hakema,b, and Razqallah Hakema,b,2 aOntario Cancer Institute, University Health Network and bDepartment of Medical Biophysics, University of Toronto, Toronto, M5G 2M9 ON, Canada; cThe Hospital for Sick Children, Toronto, M5G 2L3 ON, Canada; dDepartment of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; and eCancer Research UK, Institute for Cancer Studies, Birmingham University, Birmingham B15 2TT, United Kingdom Edited* by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved November 14, 2013 (received for review October 30, 2013) Defective signaling or repair of DNA double-strand breaks has X–MDC1–RNF8 axis, RNF168 also functions in DSB signaling been associated with developmental defects and human diseases. independently of this pathway. Therefore, we postulated that The E3 ligase RING finger 168 (RNF168), mutated in the human RNF168 also might regulate DSB signaling through direct radiosensitivity, immunodeficiency, dysmorphic features, and modulation of 53BP1 functions. learning difficulties syndrome, was shown to ubiquitylate H2A- In the present study, we demonstrate that RNF168 associates γ – – type histones, and this ubiquitylation was proposed to facilitate with 53BP1 independently of the -H2A.X MDC1 RNF8 sig- the recruitment of p53-binding protein 1 (53BP1) to the sites of naling axis. RNF168 ubiquitylates 53BP1 before its localization DNA double-strand breaks. In contrast to more upstream proteins to DSB sites, and this ubiquitylation is important for the initial signaling DNA double-strand breaks (e.g., RNF8), deficiency of recruitment of 53BP1 to DSB sites and its function in non- homologous end joining (NHEJ) and activation of checkpoints. -
DNA Damage Alters Nuclear Mechanics Through Chromatin Reorganisation
bioRxiv preprint doi: https://doi.org/10.1101/2020.07.10.197517; this version posted July 11, 2020. 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. DNA damage alters nuclear mechanics through chromatin reorganisation Ália dos Santos1, Alexander W. Cook1, Rosemarie E Gough1, Martin Schilling2, Nora Aleida Olszok2, Ian Brown3, Lin Wang4, Jesse Aaron5, Marisa L. Martin-Fernandez4, Florian Rehfeldt2,6* and Christopher P. Toseland1* 1Department of Oncology and Metabolism, University of Sheffield, Sheffield, S10 2RX, UK.2University of Göttingen, 3rd Institute of Physics – Biophysics, Göttingen, 37077, Germany. 3School of Biosciences, University of Kent, Canterbury, CT2 7NJ, UK. 4Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell, Didcot, Oxford OX11 0QX, UK. 5Advanced Imaging Center, HHMI Janelia Research Campus, Ashburn, USA. 6University of Bayreuth, Experimental Physics 1, Bayreuth, 95440, Germany. *Corresponding Authors: Florian Rehfeldt [email protected] & Christopher P. Toseland [email protected] Key words: Mechanics, DNA damage, DNA organisation, Nucleus ABSTRACT Cisplatin, specifically, creates adducts within the DNA double-strand breaks (DSBs) drive genomic double helix, which then lead to double-strand instability. For efficient and accurate repair of breaks (DSBs) in the DNA during replication, these DNA lesions, the cell activates DNA through replication-fork collapse3. damage repair pathways. However, it remains DSBs can result in large genomic aberrations and unknown how these processes may affect the are, therefore, the most deleterious to the cell. -
MDC1 and RNF8 Function in a Pathway That Directs BRCA1
Research Article 6049 MDC1 and RNF8 function in a pathway that directs BRCA1-dependent localization of PALB2 required for homologous recombination Fan Zhang1, Gregory Bick1, Jung-Young Park1 and Paul R. Andreassen1,2,* 1Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Research Foundation, Cincinnati, OH 45229, USA 2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA *Author for correspondence ([email protected]) Accepted 6 September 2012 Journal of Cell Science 125, 6049–6057 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.111872 Summary The PALB2 protein is associated with breast cancer susceptibility and Fanconi anemia. Notably, PALB2 is also required for DNA repair by homologous recombination (HR). However, the mechanisms that regulate PALB2, and the functional significance of its interaction with the BRCA1 breast cancer susceptibility protein, are poorly understood. Here, to better understand these processes, we fused PALB2, or the PALB2(L21P) mutant which cannot bind to BRCA1, with the BRCT repeats that are present in, and which localize, BRCA1. Our results yield important insights into the regulation of PALB2 function. Both fusion proteins can bypass BRCA1 to localize to sites of DNA damage. Further, the localized fusion proteins are functional, as determined by their ability to support the assembly of RAD51 foci, even in the absence of the capacity of PALB2 to bind BRCA1. Strikingly, the localized fusion proteins mediate DNA double-strand break (DSB)-initiated HR and resistance to mitomycin C in PALB2-deficient cells. Additionally, we show that the BRCA1–PALB2 heterodimer, rather than the PALB2–PALB2 homodimer, mediates these responses. -
Staining, and in Situ Digestion with Restriction Endonucleases
Heredity66 (1991) 403—409 Received 23 August 1990 Genetical Society of Great Britain An analysis of coho salmon chromatin by means of C-banding, AG- and fluorochrome staining, and in situ digestion with restriction endonucleases R. LOZANO, C. RUIZ REJON* & M. RUIZ REJON* Departamento de Biologia Animal, Ecologia y Genética. E. /ngenierIa T. AgrIcola, Campus Universitario de Almeria, 04120 AlmerIa and *Facu/tad de Ciencias, 18071 Granada, Universidad de Granada, Spain Thechromosome complement of the coho salmon (Oncorhynchus kisutch) has been analysed by means of C-banding, silver and fluorochrome staining, and in situ digestion with restriction endo- nucleases. C-banding shows heterochromatic regions in the centromeres of most chromosomes but not in the telomeric areas. The fifteenth metacentric chromosome pair contains a large block of constitutive heterochromatin, which occupies almost all of one chromosome arm. This region is also the site where the ribosomal cistrons are located and it reacts positively to CMA3/DA fluorochrome staining. The NORs are subject to chromosome polymorphism, which might be explicable in terms of an amplification of ribosomal cistrons. The digestion banding patterns produced by four types of restriction endonucleases on the euchromatic and heterochromatic regions are described. Two kinds of highly repetitive DNAs can be distinguished and the role of restriction endonucleases as a valuable tool in chromosome characterization studies, as well as in the analysis of the structure and organization of fish chromatin, are also discussed. Keywords:C-banding,coho salmon, fluorochrome staining, restriction endonuclease banding. (Oncorhynchus kisutch), as well as applying conven- Introduction tional banding techniques, we have analysed the Theuse of restriction endonucleases (REs) is becom- mitotic chromosomes using DNA base-pair-specific ing common not only in molecular biology but also as fluorochromes and in situ digestion with restriction an important tool in molecular cytogenetics. -
In Silico Analysis of the TANC Protein Family Received: 3 November 2015 Alessandra Gasparini1,2, Silvio C
www.nature.com/scientificreports OPEN Dynamic scafolds for neuronal signaling: in silico analysis of the TANC protein family Received: 3 November 2015 Alessandra Gasparini1,2, Silvio C. E. Tosatto 2,3, Alessandra Murgia1,4 & Emanuela Leonardi1 Accepted: 2 June 2017 The emergence of genes implicated across multiple comorbid neurologic disorders allows to identify Published online: 28 July 2017 shared underlying molecular pathways. Recently, investigation of patients with diverse neurologic disorders found TANC1 and TANC2 as possible candidate disease genes. While the TANC proteins have been reported as postsynaptic scafolds infuencing synaptic spines and excitatory synapse strength, their molecular functions remain unknown. Here, we conducted a comprehensive in silico analysis of the TANC protein family to characterize their molecular role and understand possible neurobiological consequences of their disruption. The known Ankyrin and tetratricopeptide repeat (TPR) domains have been modeled. The newly predicted N-terminal ATPase domain may function as a regulated molecular switch for downstream signaling. Several putative conserved protein binding motifs allowed to extend the TANC interaction network. Interestingly, we highlighted connections with diferent signaling pathways converging to modulate neuronal activity. Beyond a known role for TANC family members in the glutamate receptor pathway, they seem linked to planar cell polarity signaling, Hippo pathway, and cilium assembly. This suggests an important role in neuron projection, extension and diferentiation. Neurodevelopmental disorders (NDDs) are common conditions including clinically and genetically heteroge- neous diseases, such as intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy1. Advances in next generation sequencing have identifed a large number of newly arising disease mutations which disrupt convergent molecular pathways involved in neuronal plasticity and synaptic strength2–6.