A Genetic Map of the Response to DNA Damage in Human Cells
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Extreme HOT Regions Are Cpg-Dense Promoters in C. Elegans and Humans
Research Extreme HOT regions are CpG-dense promoters in C. elegans and humans Ron A.-J. Chen, Przemyslaw Stempor, Thomas A. Down, Eva Zeiser, Sky K. Feuer, and Julie Ahringer1 The Gurdon Institute and Department of Genetics, University of Cambridge, Cambridge CB3 0DH, United Kingdom Most vertebrate promoters lie in unmethylated CpG-dense islands, whereas methylation of the more sparsely distributed CpGs in the remainder of the genome is thought to contribute to transcriptional repression. Nonmethylated CG di- nucleotides are recognized by CXXC finger protein 1 (CXXC1, also known as CFP1), which recruits SETD1A (also known as Set1) methyltransferase for trimethylation of histone H3 lysine 4, an active promoter mark. Genomic regions enriched for CpGs are thought to be either absent or irrelevant in invertebrates that lack DNA methylation, such as C. elegans; however, a CXXC1 ortholog (CFP-1) is present. Here we demonstrate that C. elegans CFP-1 targets promoters with high CpG density, and these promoters are marked by high levels of H3K4me3. Furthermore, as for mammalian promoters, high CpG content is associated with nucleosome depletion irrespective of transcriptional activity. We further show that highly occupied target (HOT) regions identified by the binding of a large number of transcription factors are CpG-rich pro- moters in C. elegans and human genomes, suggesting that the unusually high factor association at HOT regions may be a consequence of CpG-linked chromatin accessibility. Our results indicate that nonmethylated CpG-dense sequence is a conserved genomic signal that promotes an open chromatin state, targeting by a CXXC1 ortholog, and H3K4me3 modification in both C. -
BRIP1, BRCA1 Interacting Protein C-Terminal Helicase 1 Polyclonal Antibody
BRIP1, BRCA1 interacting protein C-terminal helicase 1 polyclonal antibody RCA1 interacts in vivo with BRCA1 interacting protein C-terminal helicase 1 (BRIP1) also called BACH1, is a member of the or Research Use Only. Not for B FDiagnostic or Therapeutic Use. RecQ DEAH helicase family and interacts with the BRCT repeats of Purchase does not include or carry the breast cancer type 1 protein (BRCA1). Helicases of the RecQ any right to resell or transfer this DEAH family have been shown to be important for the maintenance product either as a stand-alone of genomic integrity in prokaryotes and eukaryotes. Members of this product or as a component of another family are genes responsible for cancer predisposition disorders like product. Any use of this product other Bloom’s syndrome, Werner’s syndrome and Rothmund-Thomson than the permitted use without the syndrome. The BRCA1/BRIP complex is important in the normal express written authorization of Allele double-strand break repair function of BRCA1. Since mutations in Biotech is strictly prohibited BRIP1 interfere with normal double-strand break repair in a manner that is dependent on its BRCA1 binding function, BRIP1 may be a target of germline cancer-inducing mutations. Website: www.allelebiotech.com Buffers Call: 1-800-991-RNAi/858-587-6645 (Pacific Time: 9:00AM~5:00PM) Purified rabbit polyclonal antibody supplied in PBS with 0.09% (W/V) Email: [email protected] sodium azide. This antibody is purified through a protein G column and eluted out with both high and low pH buffers and neutralized immediately after elution then followed by dialysis against PBS. -
A Novel Breast Cancer ^ Associated BRIP1 (FANCJ/BACH1) Germ- Line Mutation Impairs Protein Stability and Function
Cancer Prevention and Susceptibility A Novel Breast Cancer ^ Associated BRIP1 (FANCJ/BACH1)Germ- line Mutation Impairs Protein Stability and Function Arcangela De Nicolo,1MariellaTancredi,4 Grazia Lombardi,4 Cristina Chantal Flemma,4 Serena Barbuti,4 Claudio Di Cristofano,4 Bijan Sobhian,1Generoso Bevilacqua,4 Ronny Drapkin,2,3 andMariaAdelaideCaligo4 Abstract Purpose: BRCA1-interacting protein 1 (BRIP1; FANCJ/BACH1), which encodes a DNA helicase that interacts with BRCA1, has been suggested to be a low-penetrance breast cancer predispos- ing gene.We aimed to assess whether BRIP1 mutations contribute to breast cancer susceptibility in our population and, if so, to investigate the effect of such mutation(s) on BRIP1function. Experimental Design: A series of49 breast/ovarian cancer families, devoid ofa BRCA1/ BRCA2 mutation, were screened for BRIP1 mutations. Functional analyses, including coimmuno- precipitation and stability assays, were employed to further characterize a previously unreported variant. Results: Five sequence alterations were identified, of which four had been already described. Herein, we report a novel BRIP1 germ-line mutation identified in a woman with early-onset breast cancer. The mutation consists ofa 4-nucleotide deletion (c.2992-2995delAAGA) in BRIP1 exon 20 that causes a shift in the reading frame, disrupts the BRCA1-binding domain of BRIP1, and creates a premature stop codon. Functional analysis ofthe recombinant mutant protein in transfected cells showed that the truncation interferes with the stability of the protein and with its ability to interact with BRCA1. Loss ofthe wild-type BRIP1 allele with retention ofthe mutated one was observed in the patient’s breast tumor tissue. Conclusions: These results, by showing that the newly identified BRIP1 c.2992-2995delAAGA mutation is associated with instability and functional impairment of the encoded protein, provide further evidence of a breast cancer ^ related role for BRIP1. -
Analysis of Gene Expression Data for Gene Ontology
ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Master of Science Robert Daniel Macholan May 2011 ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION Robert Daniel Macholan Thesis Approved: Accepted: _______________________________ _______________________________ Advisor Department Chair Dr. Zhong-Hui Duan Dr. Chien-Chung Chan _______________________________ _______________________________ Committee Member Dean of the College Dr. Chien-Chung Chan Dr. Chand K. Midha _______________________________ _______________________________ Committee Member Dean of the Graduate School Dr. Yingcai Xiao Dr. George R. Newkome _______________________________ Date ii ABSTRACT A tremendous increase in genomic data has encouraged biologists to turn to bioinformatics in order to assist in its interpretation and processing. One of the present challenges that need to be overcome in order to understand this data more completely is the development of a reliable method to accurately predict the function of a protein from its genomic information. This study focuses on developing an effective algorithm for protein function prediction. The algorithm is based on proteins that have similar expression patterns. The similarity of the expression data is determined using a novel measure, the slope matrix. The slope matrix introduces a normalized method for the comparison of expression levels throughout a proteome. The algorithm is tested using real microarray gene expression data. Their functions are characterized using gene ontology annotations. The results of the case study indicate the protein function prediction algorithm developed is comparable to the prediction algorithms that are based on the annotations of homologous proteins. -
Annexina7 and CAP1 Are Associated with Regulating Tumor Cell Adhesion Molecule Expression and Biological Behavior
AnnexinA7 and CAP1 are associated with regulating tumor cell adhesion molecule expression and biological behavior Type Research paper Keywords hepatocellular carcinoma, adhesion molecule, AnnexinA7, CAP1, Biological behaviors Abstract Introduction To find out the correlations between the effects of down-regulating AnnexinA7 and CAP1 gene on cell adhesion factors and the biological behavior of Hca-p cells cells, and finally infer the relationship between the two genes. Material and methods Western blot ,qRT-PCR,immunocytochemistry, CCK8 cell proliferation, flow cytometry, lymph node adhesion and transwell chamber assay testing . Results AnnexinA7 and CAP1 were consistent with the regulation of the expression of the adhesion molecules such as FAK, Src, Paxillin and E-cadherin. At the mRNA and protein levels, the expression of FAK, Src and Paxillin were increased with down-regulated AnnexinA7 and CAP1 genes, while E-cadherin was down-regulated in the change of these two genes. And the low expression of AnnexinA7 could affect the expression of CAP1 in mRNA and protein levels. otherwise, the localization of AnnexinA7 and CAP1 in hepatocellular carcinoma cells was also the same. After down-regulating the expression of CAP1, the functions of proliferation, lymph node adhesion and invasion were increased and earlyPreprint apoptotic ability was decreased in Hca-P cells. Conclusions AnnexinA7 and CAP1 could control the expression of these adhesion molecules in the same trend. We speculated they may be co-localization. And AnnexinA7 gene may be related to the molecular mechanism of CAP1 gene, which is likely to have a consistent effect on cell adhesion molecules and be closely related to the biological behaviors of Hca-P cells.AnnexinA7 and CAP1 may play an inhibitory role in lymph node metastasis to provide a reliable basis for the early identification of lymphatic metastasis in hepatocellular carcinoma. -
The Structural Basis for Selective Binding of Non-Methylated Cpg Islands by the CFP1 CXXC Domain
ARTICLE Received 13 Dec 2010 | Accepted 9 Feb 2011 | Published 8 Mar 2011 DOI: 10.1038/ncomms1237 The structural basis for selective binding of non-methylated CpG islands by the CFP1 CXXC domain Chao Xu1,*, Chuanbing Bian1,*, Robert Lam1, Aiping Dong1 & Jinrong Min1,2 CFP1 is a CXXC domain-containing protein and an essential component of the SETD1 histone H3K4 methyltransferase complex. CXXC domain proteins direct different chromatin-modifying activities to various chromatin regions. Here, we report crystal structures of the CFP1 CXXC domain in complex with six different CpG DNA sequences. The crescent-shaped CFP1 CXXC domain is wedged into the major groove of the CpG DNA, distorting the B-form DNA, and interacts extensively with the major groove of the DNA. The structures elucidate the molecular mechanism of the non-methylated CpG-binding specificity of the CFP1 CXXC domain. The CpG motif is confined by a tripeptide located in a rigid loop, which only allows the accommodation of the non-methylated CpG dinucleotide. Furthermore, we demonstrate that CFP1 has a preference for a guanosine nucleotide following the CpG motif. 1 Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada. 2 Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. *These authors contributed equally to this work. Correspondence and requests for materials should be addressed to J.M. (email: [email protected]). NATURE COMMUNICATIONS | 2:227 | DOI: 10.1038/ncomms1237 | www.nature.com/naturecommunications © 2011 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms1237 pG islands contain a high density of CpG content and embrace the promoters of most genes in vertebrate genomes1. -
Gene Knockdown of CENPA Reduces Sphere Forming Ability and Stemness of Glioblastoma Initiating Cells
Neuroepigenetics 7 (2016) 6–18 Contents lists available at ScienceDirect Neuroepigenetics journal homepage: www.elsevier.com/locate/nepig Gene knockdown of CENPA reduces sphere forming ability and stemness of glioblastoma initiating cells Jinan Behnan a,1, Zanina Grieg b,c,1, Mrinal Joel b,c, Ingunn Ramsness c, Biljana Stangeland a,b,⁎ a Department of Molecular Medicine, Institute of Basic Medical Sciences, The Medical Faculty, University of Oslo, Oslo, Norway b Norwegian Center for Stem Cell Research, Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway c Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, Oslo, Norway article info abstract Article history: CENPA is a centromere-associated variant of histone H3 implicated in numerous malignancies. However, the Received 20 May 2016 role of this protein in glioblastoma (GBM) has not been demonstrated. GBM is one of the most aggressive Received in revised form 23 July 2016 human cancers. GBM initiating cells (GICs), contained within these tumors are deemed to convey Accepted 2 August 2016 characteristics such as invasiveness and resistance to therapy. Therefore, there is a strong rationale for targeting these cells. We investigated the expression of CENPA and other centromeric proteins (CENPs) in Keywords: fi CENPA GICs, GBM and variety of other cell types and tissues. Bioinformatics analysis identi ed the gene signature: fi Centromeric proteins high_CENP(AEFNM)/low_CENP(BCTQ) whose expression correlated with signi cantly worse GBM patient Glioblastoma survival. GBM Knockdown of CENPA reduced sphere forming ability, proliferation and cell viability of GICs. We also Brain tumor detected significant reduction in the expression of stemness marker SOX2 and the proliferation marker Glioblastoma initiating cells and therapeutic Ki67. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
DNA Damage Response
biomolecules Editorial DNA Damage Response Valentyn Oksenych 1,2,3,4,* and Denis E. Kainov 1,5,* 1 Department for Cancer Research and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway 2 Department of Biosciences and Nutrition (BioNuT), Karolinska Institutet, 14183 Huddinge, Sweden 3 KG Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway 4 Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway 5 Institute of Technology, University of Tartu, 50090 Tartu, Estonia * Correspondence: [email protected] (V.O.); [email protected] (D.E.K.) DNA in our cells is constantly modified by internal and external factors. For exam- ple, metabolic byproducts, ionizing radiation (IR), ultraviolet (UV) light, and medicines can induce spontaneous DNA lesions [1–3]. However, DNA modifications can also be programmed. In particular, the recombination activating gene (RAG) can induce breaks generated during the V(D)J recombination in developing B and T lymphocytes [1,2]. In addition, activation-induced cytidine deaminase (AID) makes DNA break during the class-switch recombination (CSR) and somatic hypermutation (SHM) in B cells [1,2]. One focus of this Special Issue is on the non-homologous end-joining (NHEJ) DNA repair pathway and DNA repair and DNA damage response (DDR) factors. Oksenych et al. and others found the functional redundancy of these factors in mammalian cells. In particu- lar, a genetic interaction was found between the X-ray repair cross-complementing protein 4 (XRCC4)-like factor (XLF, also known as Cernunnos) and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [4,5], the paralog of XRCC4 and XLF (PAXX) [6–9], and the modulator of retrovirus infection (MRI, also known as Cyren) [10]. -
PDF Output of CLIC (Clustering by Inferred Co-Expression)
PDF Output of CLIC (clustering by inferred co-expression) Dataset: Num of genes in input gene set: 13 Total number of genes: 16493 CLIC PDF output has three sections: 1) Overview of Co-Expression Modules (CEMs) Heatmap shows pairwise correlations between all genes in the input query gene set. Red lines shows the partition of input genes into CEMs, ordered by CEM strength. Each row shows one gene, and the brightness of squares indicates its correlations with other genes. Gene symbols are shown at left side and on the top of the heatmap. 2) Details of each CEM and its expansion CEM+ Top panel shows the posterior selection probability (dataset weights) for top GEO series datasets. Bottom panel shows the CEM genes (blue rows) as well as expanded CEM+ genes (green rows). Each column is one GEO series dataset, sorted by their posterior probability of being selected. The brightness of squares indicates the gene's correlations with CEM genes in the corresponding dataset. CEM+ includes genes that co-express with CEM genes in high-weight datasets, measured by LLR score. 3) Details of each GEO series dataset and its expression profile: Top panel shows the detailed information (e.g. title, summary) for the GEO series dataset. Bottom panel shows the background distribution and the expression profile for CEM genes in this dataset. Overview of Co-Expression Modules (CEMs) with Dataset Weighting Scale of average Pearson correlations Num of Genes in Query Geneset: 13. Num of CEMs: 1. 0.0 0.2 0.4 0.6 0.8 1.0 Cenpk Cenph Cenpp Cenpu Cenpn Cenpq Cenpl Apitd1 -
Interconversion Between Active and Inactive TATA-Binding Protein
1446–1459 Nucleic Acids Research, 2012, Vol. 40, No. 4 Published online 19 October 2011 doi:10.1093/nar/gkr802 Interconversion between active and inactive TATA-binding protein transcription complexes in the mouse genome Mohamed-Amin Choukrallah, Dominique Kobi1, Igor Martianov1, W. W. M. Pim Pijnappel2,4, Nikolai Mischerikow2,3, Tao Ye1, Albert J. R. Heck3,4,5, H. Th. Marc Timmers2,4 and Irwin Davidson1,* 1Institut de Ge´ ne´ tique et de Biologie Mole´ culaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, 67404 Illkirch Ce´ dex, France, 2Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 4Netherlands Proteomics Centre and 5Centre for Biomedical Genetics, Padualaan 8, 3584 CH Utrecht, The Netherlands Received June 10, 2011; Revised September 12, 2011; Accepted September 13, 2011 ABSTRACT preinitiation complex comprising B-TFIID that primes the promoter for productive preinitiation The TATA binding protein (TBP) plays a pivotal role complex formation in mammalian cells. in RNA polymerase II (Pol II) transcription through incorporation into the TFIID and B-TFIID complexes. The role of mammalian B-TFIID composed of TBP INTRODUCTION and B-TAF1 is poorly understood. Using a com- Accurate initiation of transcription by RNA polymerase plementation system in genetically modified mouse II (Pol II) requires the assembly of the multiprotein cells where endogenous TBP can be condi- preinitiation complex (PIC) on the core promoter around tionally inactivated and replaced by exogenous the mRNA start site (1–3). Amongst the basal transcrip- mutant TBP coupled to tandem affinity purification tion factors in this process is the TFIID complex com- and mass spectrometry, we identify two TBP prising the TATA binding protein (TBP) and a set of 13–14 TBP-associated factors (TAFs) (4–7). -
Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri/Cyren
biomolecules Article Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri/Cyren 1,2, 1,2, 1,2, 1,2 Sergio Castañeda-Zegarra y , Camilla Huse y, Øystein Røsand y, Antonio Sarno , Mengtan Xing 1,2, Raquel Gago-Fuentes 1,2, Qindong Zhang 1,2, Amin Alirezaylavasani 1,2, Julia Werner 1,2,3, Ping Ji 1, Nina-Beate Liabakk 1, Wei Wang 1, Magnar Bjørås 1,2 and Valentyn Oksenych 1,2,4,* 1 Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway; [email protected] (S.C.-Z.); [email protected] (C.H.); [email protected] (Ø.R.); [email protected] (A.S.); [email protected] (M.X.); [email protected] (R.G.-F.); [email protected] (Q.Z.); [email protected] (A.A.); [email protected] (J.W.); [email protected] (P.J.); [email protected] (N.-B.L.); [email protected] (W.W.); [email protected] (M.B.) 2 St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway 3 Molecular Biotechnology MS programme, Heidelberg University, 69120 Heidelberg, Germany 4 Department of Biosciences and Nutrition (BioNut), Karolinska Institutet, 14183 Huddinge, Sweden * Correspondence: [email protected]; Tel.: +47-913-43-084 These authors contributed equally to this work. y Received: 7 November 2019; Accepted: 26 November 2019; Published: 28 November 2019 Abstract: Classical non-homologous end joining (NHEJ) is a molecular pathway that detects, processes, and ligates DNA double-strand breaks (DSBs) throughout the cell cycle.