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Escape from X Chromosome Inactivation Is an Intrinsic Property of the Jarid1c Locus
Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus Nan Lia,b and Laura Carrela,1 aDepartment of Biochemistry and Molecular Biology and bIntercollege Graduate Program in Genetics, Pennsylvania State College of Medicine, Hershey, PA 17033 Edited by Stanley M. Gartler, University of Washington, Seattle, WA, and approved September 23, 2008 (received for review August 8, 2008) Although most genes on one X chromosome in mammalian fe- Sequences on the X are hypothesized to propagate XCI (12) and males are silenced by X inactivation, some ‘‘escape’’ X inactivation to be depleted at escape genes (8, 9). LINE-1 repeats fit such and are expressed from both active and inactive Xs. How these predictions, particularly on the human X (8–10). Distinct dis- escape genes are transcribed from a largely inactivated chromo- tributions of other repeats classify some mouse X genes (5). some is not fully understood, but underlying genomic sequences X-linked transgenes also test the role of genomic sequences in are likely involved. We developed a transgene approach to ask escape gene expression. Most transgenes are X-inactivated, whether an escape locus is autonomous or is instead influenced by although a number escape XCI (e.g., refs. 13 and 14). Such X chromosome location. Two BACs carrying the mouse Jarid1c gene transgene studies indicate that, in addition to CTCF (6), locus and adjacent X-inactivated transcripts were randomly integrated control regions and matrix attachment sites are also not suffi- into mouse XX embryonic stem cells. Four lines with single-copy, cient to escape XCI (15, 16). -
SF3B3) and Sin3a Associated Protein 130 (SAP130
cells Communication Ambiguity about Splicing Factor 3b Subunit 3 (SF3B3) and Sin3A Associated Protein 130 (SAP130) Paula I. Metselaar 1,* , Celine Hos 1, Olaf Welting 1, Jos A. Bosch 2,3, Aletta D. Kraneveld 4 , Wouter J. de Jonge 1 and Anje A. Te Velde 1 1 Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam UMC, University of Amsterdam, 1105BK Amsterdam, The Netherlands; [email protected] (C.H.); [email protected] (O.W.); [email protected] (W.J.d.J.); [email protected] (A.A.T.V.) 2 Department of Psychology, University of Amsterdam, 1018WS Amsterdam, The Netherlands; [email protected] 3 Department of Medical Psychology, Amsterdam UMC, University of Amsterdam, 1001NK Amsterdam, The Netherlands 4 Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584CG Utrecht, The Netherlands; [email protected] * Correspondence: [email protected] Abstract: In 2020, three articles were published on a protein that can activate the immune system by binding to macrophage-inducible C-type lectin receptor (Mincle). In the articles, the protein was referred to as ‘SAP130, a subunit of the histone deacetylase complex.’ However, the Mincle ligand the authors aimed to investigate is splicing factor 3b subunit 3 (SF3B3). This splicing factor is unrelated to SAP130 (Sin3A associated protein 130, a subunit of the histone deacetylase-dependent Sin3A corepressor complex). The conclusions in the three articles were formulated for SF3B3, Citation: Metselaar, P.I.; Hos, C.; while the researchers used qPCR primers and antibodies against SAP130. -
DDB1 Targets Chk1 to the Cul4 E3 Ligase Complex in Normal Cycling Cells and in Cells Experiencing Replication Stress
Published OnlineFirst March 10, 2009; DOI: 10.1158/0008-5472.CAN-08-3382 Research Article DDB1 Targets Chk1 to the Cul4 E3 Ligase Complex in Normal Cycling Cells and in Cells Experiencing Replication Stress Van Leung-Pineda,1 Jiwon Huh,1 and Helen Piwnica-Worms1,2,3 Departments of 1Cell Biology and Physiology and 2Internal Medicine and 3Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri Abstract protein FANCE (8, 10–12). Chk1 carries out its functions both in the The Chk1 protein kinase preserves genome integrity in normal nucleus and at the centrosome (13). Drugs that block Chk1 kinase proliferating cells and in cells experiencing replicative and activity or enhance its proteolysis by interfering with binding to genotoxic stress. Chk1 is currently being targeted in antican- heat shock protein 90 (HSP90) are currently being tested as cer regimens. Here, we identify damaged DNA-binding protein anticancer agents (14–17). 1 (DDB1) as a novel Chk1-interacting protein. DDB1 is part of Chk1 is regulated by reversible phosphorylation and by an E3 ligase complex that includes the cullin proteins Cul4A ubiquitin-mediated proteolysis. Under periods of replicative stress, and Cul4B. We report that Cul4A/DDB1 negatively regulates the ATRIP/ATR module binds to single-stranded DNA and, Chk1 stability in vivo. Chk1 associates with Cul4A/DDB1 together with Rad17 and the 9-1-1 complex, activates Chk1 in a Claspin-dependent manner (18–22). ATR directly phosphorylates during an unperturbed cell division cycle and both Chk1 317 345 phosphorylation and replication stress enhanced these inter- Chk1 on two COOH-terminal residues: Ser (S317) and Ser actions. -
The Role and Mechanism of CRL4 E3 Ubiquitin Ligase in Cancer and Its Potential Therapy Implications
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 40 The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications Youzhou Sang1,3,4, Fan Yan1,3,4 and Xiubao Ren2,3,4 1 Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China 2 Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China 3 National Clinical Research Center of Cancer, Tianjin, China 4 Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China Correspondence to: Xiubao Ren, email: [email protected] Keywords: CRL4, CUL4, ubiquitination, cancer Received: April 08, 2015 Accepted: September 23, 2015 Published: October 09, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT CRLs (Cullin-RING E3 ubiquitin ligases) are the largest E3 ligase family in eukaryotes, which ubiquitinate a wide range of substrates involved in cell cycle regulation, signal transduction, transcriptional regulation, DNA damage response, genomic integrity, tumor suppression and embryonic development. CRL4 E3 ubiquitin ligase, as one member of CRLs family, consists of a RING finger domain protein, cullin4 (CUL4) scaffold protein and DDB1–CUL4 associated substrate receptors. The CUL4 subfamily includes two members, CUL4A and CUL4B, which share extensively sequence identity and functional redundancy. Aberrant expression of CUL4 has been found in a majority of tumors. Given the significance of CUL4 in cancer, understanding its detailed aspects of pathogenesis of human malignancy would have significant value for the treatment of cancer. -
Systems Analysis Implicates WAVE2&Nbsp
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL.5,NO.4,2020 ª 2020 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/). PRECLINICAL RESEARCH Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects a b b b Jonathan J. Edwards, MD, Andrew D. Rouillard, PHD, Nicolas F. Fernandez, PHD, Zichen Wang, PHD, b c d d Alexander Lachmann, PHD, Sunita S. Shankaran, PHD, Brent W. Bisgrove, PHD, Bradley Demarest, MS, e f g h Nahid Turan, PHD, Deepak Srivastava, MD, Daniel Bernstein, MD, John Deanfield, MD, h i j k Alessandro Giardini, MD, PHD, George Porter, MD, PHD, Richard Kim, MD, Amy E. Roberts, MD, k l m m,n Jane W. Newburger, MD, MPH, Elizabeth Goldmuntz, MD, Martina Brueckner, MD, Richard P. Lifton, MD, PHD, o,p,q r,s t d Christine E. Seidman, MD, Wendy K. Chung, MD, PHD, Martin Tristani-Firouzi, MD, H. Joseph Yost, PHD, b u,v Avi Ma’ayan, PHD, Bruce D. Gelb, MD VISUAL ABSTRACT Edwards, J.J. et al. J Am Coll Cardiol Basic Trans Science. 2020;5(4):376–86. ISSN 2452-302X https://doi.org/10.1016/j.jacbts.2020.01.012 JACC: BASIC TO TRANSLATIONALSCIENCEVOL.5,NO.4,2020 Edwards et al. 377 APRIL 2020:376– 86 WAVE2 Complex in LVOTO HIGHLIGHTS ABBREVIATIONS AND ACRONYMS Combining CHD phenotype–driven gene set enrichment and CRISPR knockdown screening in zebrafish is an effective approach to identifying novel CHD genes. -
Loss of Fam60a, a Sin3a Subunit, Results in Embryonic Lethality and Is Associated with Aberrant Methylation at a Subset of Gene
RESEARCH ARTICLE Loss of Fam60a, a Sin3a subunit, results in embryonic lethality and is associated with aberrant methylation at a subset of gene promoters Ryo Nabeshima1,2, Osamu Nishimura3,4, Takako Maeda1, Natsumi Shimizu2, Takahiro Ide2, Kenta Yashiro1†, Yasuo Sakai1, Chikara Meno1, Mitsutaka Kadota3,4, Hidetaka Shiratori1†, Shigehiro Kuraku3,4*, Hiroshi Hamada1,2* 1Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan; 2Laboratory for Organismal Patterning, RIKEN Center for Developmental Biology, Kobe, Japan; 3Phyloinformatics Unit, RIKEN Center for Life Science Technologies, Kobe, Japan; 4Laboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan Abstract We have examined the role of Fam60a, a gene highly expressed in embryonic stem cells, in mouse development. Fam60a interacts with components of the Sin3a-Hdac transcriptional corepressor complex, and most Fam60a–/– embryos manifest hypoplasia of visceral organs and die in utero. Fam60a is recruited to the promoter regions of a subset of genes, with the expression of these genes being either up- or down-regulated in Fam60a–/– embryos. The DNA methylation level of the Fam60a target gene Adhfe1 is maintained at embryonic day (E) 7.5 but markedly reduced at –/– *For correspondence: E9.5 in Fam60a embryos, suggesting that DNA demethylation is enhanced in the mutant. [email protected] (SK); Examination of genome-wide DNA methylation identified several differentially methylated regions, [email protected] (HH) which were preferentially hypomethylated, in Fam60a–/– embryos. Our data suggest that Fam60a is †These authors contributed required for proper embryogenesis, at least in part as a result of its regulation of DNA methylation equally to this work at specific gene promoters. -
Hyperphosphorylation Repurposes the CRL4B E3 Ligase to Coordinate Mitotic Entry and Exit
Research Collection Doctoral Thesis Identification and Characterization of Novel Cullin 4-based E3 Ligases in Somatic Cell Division Author(s): da Graça Gilberto, Samuel Filipe Publication Date: 2017 Permanent Link: https://doi.org/10.3929/ethz-b-000219014 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 24583 Identification and characterization of novel Cullin 4-based E3 ligases in somatic cell division A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich) Presented by SAMUEL FILIPE DA GRAÇA GILBERTO MSc in Biochemistry, University of Lisbon Born on 21.02.1988 Citizen of Portugal Accepted on the recommendation of Prof. Dr. Matthias Peter Prof. Dr. Anton Wutz 2017 Table of contents 1. General introduction ..................................................................................................................1 1.1. The ubiquitylation machinery ....................................................................................................... 1 1.2. Principles of cell cycle regulation: a focus on CRLs and the APC/C .............................................. 3 1.3. Cullin-4 RING E3 ligases: cell-cycle regulation and beyond ........................................................ 14 1.4. Functional distinctions between CUL4A and CUL4B .................................................................. -
And CAND1-Dependent Remodelling of the Budding Yeast SCF Complex
ARTICLE Received 31 Jan 2013 | Accepted 20 Feb 2013 | Published 27 Mar 2013 DOI: 10.1038/ncomms2628 OPEN CSN- and CAND1-dependent remodelling of the budding yeast SCF complex Aleksandra Zemla1, Yann Thomas1, Sylwia Kedziora1, Axel Knebel1, Nicola T Wood1, Gwenae¨l Rabut2 & Thimo Kurz1 Cullin–RING ligases (CRLs) are ubiquitin E3 enzymes with variable substrate-adaptor and -receptor subunits. All CRLs are activated by modification of the cullin subunit with the ubiquitin-like protein Nedd8 (neddylation). The protein CAND1 (Cullin-associated-Nedd8- dissociated-1) also promotes CRL activity, even though it only interacts with inactive ligase complexes. The molecular mechanism underlying this behaviour remains largely unclear. Here, we find that yeast SCF (Skp1–Cdc53–F-box) Cullin–RING complexes are remodelled in a CAND1-dependent manner, when cells are switched from growth in fermentable to non-fermentable carbon sources. Mechanistically, CAND1 promotes substrate adaptor release following SCF deneddylation by the COP9 signalosome (CSN). CSN- or CAND1- mutant cells fail to release substrate adaptors. This delays the formation of new complexes during SCF reactivation and results in substrate degradation defects. Our results shed light on how CAND1 regulates CRL activity and demonstrate that the cullin neddylation– deneddylation cycle is not only required to activate CRLs, but also to regulate substrate specificity through dynamic substrate adaptor exchange. 1 Scottish Institute for Cell Signalling, Protein Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK. 2 CNRS, Universite´ Rennes 1, Institut de Ge´ne´tique et De´veloppement de Rennes, 2 avenue du Professeur Le´on Bernard, CS 34317, Rennes Cedex 35043, France. -
Fine-Scale Survey of X Chromosome Copy Number Variants and Indels Underlying Intellectual Disability
ARTICLE Fine-Scale Survey of X Chromosome Copy Number Variants and Indels Underlying Intellectual Disability Annabel C. Whibley,1 Vincent Plagnol,1,2 Patrick S. Tarpey,3 Fatima Abidi,4 Tod Fullston,5,6 Maja K. Choma,1 Catherine A. Boucher,1 Lorraine Shepherd,1 Lionel Willatt,7 Georgina Parkin,7 Raffaella Smith,3 P. Andrew Futreal,3 Marie Shaw,8 Jackie Boyle,9 Andrea Licata,4 Cindy Skinner,4 Roger E. Stevenson,4 Gillian Turner,9 Michael Field,9 Anna Hackett,9 Charles E. Schwartz,4 Jozef Gecz,5,6,8 Michael R. Stratton,3 and F. Lucy Raymond1,* Copy number variants and indels in 251 families with evidence of X-linked intellectual disability (XLID) were investigated by array comparative genomic hybridization on a high-density oligonucleotide X chromosome array platform. We identified pathogenic copy number variants in 10% of families, with mutations ranging from 2 kb to 11 Mb in size. The challenge of assessing causality was facilitated by prior knowledge of XLID-associated genes and the ability to test for cosegregation of variants with disease through extended pedigrees. Fine-scale analysis of rare variants in XLID families leads us to propose four additional genes, PTCHD1, WDR13, FAAH2, and GSPT2,as candidates for XLID causation and the identification of further deletions and duplications affecting X chromosome genes but without apparent disease consequences. Breakpoints of pathogenic variants were characterized to provide insight into the underlying mutational mechanisms and indicated a predominance of mitotic rather than meiotic events. By effectively bridging the gap between karyotype-level investigations and X chromosome exon resequencing, this study informs discussion of alternative mutational mechanisms, such as non- coding variants and non-X-linked disease, which might explain the shortfall of mutation yield in the well-characterized International Genetics of Learning Disability (IGOLD) cohort, where currently disease remains unexplained in two-thirds of families. -
CUL4B Promotes Proliferation and Inhibits Apoptosis of Human Osteosarcoma Cells
ONCOLOGY REPORTS 32: 2047-2053, 2014 CUL4B promotes proliferation and inhibits apoptosis of human osteosarcoma cells ZHI CHEN1*, BAO-LIANG SHEN2*, QING-GE FU3*, FEI WANG1, YI-XING TANG1, CANG-LONG HOU1 and LI CHEN1 1Department of Orthopedics, Changhai Hospital Affiliated to the Second Military Medical University, Shanghai 200433; 2Department of Orthopedics, Shanghai Jiading Central Hospital, Shanghai 201800; 3Department of Emergency and Trauma, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China Received March 4, 2014; Accepted June 10, 2014 DOI: 10.3892/or.2014.3465 Abstract. Cullin 4B (CUL4B) is a component of the Introduction Cullin4B-Ring E3 ligase complex (CRL4B) that functions in proteolysis and is implicated in tumorigenesis. Here, we report Osteosarcoma is a primary bone malignancy with high rates that CUL4B is associated with tumorigenesis by promoting of metastasis, mortality and disability, and usually occurs in proliferation and inhibiting apoptosis of human osteosarcoma children and adolescents (1). The most common treatments cells. We performed RNA interference (RNAi) with a lentiviral for osteosarcoma are surgery, chemotherapy and biotherapy. vector system to silence the CUL4B gene using osteosarcoma However, the prognosis of osteosarcoma is still poor because SAOS-2 cells. The negative control included the normal of the high degree of malignancy, rapid disease progression target cells infected with the negative control virus whereas and early metastasis (2). the knockdown cells included the normal target cells trans- Gene amplification can be defined as increased copy fected with the RNAi target virus. We assessed the inhibition numbers of certain regions of the genome. Gene amplifica- resulting from the decreased expression of the CUL4B gene on tion often results in the upregulation of gene expression by the proliferation rate of SAOS-2 cells, and also evaluated the increasing the number of templates available for transcription. -
Chromatin and Epigenetics Cross-Journal Focus Chromatin and Epigenetics
EMBO Molecular Medicine cross-journal focus Chromatin and epigenetics cross-journal focus Chromatin and epigenetics EDITORS Esther Schnapp Senior Editor [email protected] | T +49 6221 8891 502 Esther joined EMBO reports in October 2008. She was awarded her PhD in 2005 at the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden, Germany, where she studied tail regeneration in the axolotl. As a post-doc she worked on muscle development in zebrafish and on the characterisation of mesoangioblasts at the Stem Cell Research Institute of the San Raffaele Hospital in Milan, Italy. Anne Nielsen Editor [email protected] | T +49 6221 8891 408 Anne received her PhD from Aarhus University in 2008 for work on miRNA processing in Joergen Kjems’ lab. As a postdoc she then went on to join Javier Martinez’ lab at IMBA in Vienna and focused on siRNA-binding proteins and non-conventional splicing in the unfolded protein response. Anne joined The EMBO Journal in 2012. Maria Polychronidou Editor [email protected] | T +49 6221 8891 410 Maria received her PhD from the University of Heidelberg, where she studied the role of nuclear membrane proteins in development and aging. During her post-doctoral work, she focused on the analysis of tissue-specific regulatory functions of Hox transcription factors using a combination of computational and genome-wide methods. Céline Carret Editor [email protected] | T +49 6221 8891 310 Céline Carret completed her PhD at the University of Montpellier, France, characterising host immunodominant antigens to fight babesiosis, a parasitic disease caused by a unicellular EMBO Apicomplexan parasite closely related to the malaria agent Plasmodium. -
Dynamic Interplay Between Locus-Specific DNA Methylation and Hydroxymethylation Regulates Distinct Biological Pathways in Prostate Carcinogenesis Shivani N
Kamdar et al. Clinical Epigenetics (2016) 8:32 DOI 10.1186/s13148-016-0195-4 RESEARCH Open Access Dynamic interplay between locus-specific DNA methylation and hydroxymethylation regulates distinct biological pathways in prostate carcinogenesis Shivani N. Kamdar1,2, Linh T. Ho1, Ken J. Kron1, Ruth Isserlin3, Theodorus van der Kwast1,4, Alexandre R. Zlotta5, Neil E. Fleshner6, Gary Bader3 and Bharati Bapat1,2* Abstract Background: Despite the significant global loss of DNA hydroxymethylation marks in prostate cancer tissues, the locus-specific role of hydroxymethylation in prostate tumorigenesis is unknown. We characterized hydroxymethylation and methylation marks by performing whole-genome next-generation sequencing in representative normal and prostate cancer-derived cell lines in order to determine functional pathways and key genes regulated by these epigenomic modifications in cancer. Results: Our cell line model shows disruption of hydroxymethylation distribution in cancer, with global loss and highly specific gain in promoter and CpG island regions. Significantly, we observed locus-specific retention of hydroxymethylation marks in specific intronic and intergenic regions which may play a novel role in the regulation of gene expression in critical functional pathways, such as BARD1 signaling and steroid hormone receptor signaling in cancer. We confirm a modest correlation of hydroxymethylation with expression in intragenic regions in prostate cancer, while identifying an original role for intergenic hydroxymethylation in differentially expressed regulatory pathways in cancer. We also demonstrate a successful strategy for the identification and validation of key candidate genes from differentially regulated biological pathways in prostate cancer. Conclusions: Our results indicate a distinct function for aberrant hydroxymethylation within each genomic feature in cancer, suggesting a specific and complex role for the deregulation of hydroxymethylation in tumorigenesis, similar to methylation.