Cul4a Promotes Zebrafish Primitive Erythropoiesis Via Upregulating Scl
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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). -
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. -
Homo-Protacs for the Chemical Knockdown of Cereblon
Homo-PROTACs for the Chemical Knockdown of Cereblon Stefanie Lindner 60th ASH Annual Meeting and Exposition December 1, 2018 San Diego , CA IMiDs modulate substrate specificity of the CRBN E3 ligase Thalidomide Lenalidomide omalidomide IKZF1 Multiple IKZF3 Myeloma CRBN Proteasomal CK1α del(5q) MDS Neo- E3 ubiquitin ligase degradation substrate SALL4 Teratogenicity Ito et al., 2010, Science Krönke et al., 2014 Science Lu et al., 2014, Science Krönke et al., 2015, Nature Donovan et al., 2018, Elife Matyskiela et al., 2018, Nat Chem Biol. Proteolysis Targeting Chimeras (PROTACs) Bifunctional molecules for degradation of proteins of interest (POI) Thalidomide POI Lenalidomide ligand Pomalidomide linker POI IMiD CRBN PROTAC Sakamoto et. al, 2001, PNAS Schneekloth et. al, 2004, J Am Chem Soc. Lu et al., 2015, Chem Biol Winter et al., 2017, Mol Cell. Proteolysis Targeting Chimeras (PROTACs) Bifunctional molecules for degradation of proteins of interest (POI) POI IMiD CRBN Proteasomal PROTAC degradation Sakamoto et. al, 2001, PNAS Schneekloth et. al, 2004, J Am Chem Soc. Lu et al., 2015, Chem Biol Winter et al., 2017, Mol Cell. Homodimeric pomalidomide-based PROTACs Linker (size X) O O O HN O O NH O O HN NH O N N O Homo-bifunctional molecules O O Chemical Formula: C36H40N6O11 Molecular Weight: 732,75 Pomalidomide Pomalidomide Chemically CRBN Pom Pom CRBN induced CRBN knockdown Proteasomal POI = CRBN degradation Homodimeric pomalidomide-based PROTACs corresponding linker substructures No. of linear CRBN IKZF1 Linker linker atoms degradation degradation -
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 .................................................................. -
The CUL4A Ubiquitin Ligase Is a Potential Therapeutic Target in Skin Cancer and Other Malignancies
Chinese Journal of Cancer Review The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies Jeffrey Hannah1 and Peng-Bo Zhou1,2 Abstract Cullin 4A (CUL4A) is an E3 ubiquitin ligase that directly affects DNA repair and cell cycle progression by targeting substrates including damage-specific DNA-binding protein 2 (DDB2), xeroderma pigmentosum complementation group C (XPC), chromatin licensing and DNA replication factor 1 (Cdt1), and p21. Recent work from our laboratory has shown that Cul4a-deficient mice have greatly reduced rates of ultraviolet-induced skin carcinomas. On a cellular level, Cul4a-deficient cells have great capacity for DNA repair and demonstrate a slow rate of proliferation due primarily to increased expression of DDB2 and p21, respectively. This suggests that CUL4A promotes tumorigenesis (as well as accumulation of skin damage and subsequent premature aging) by limiting DNA repair activity and expediting S phase entry. In addition, CUL4A has been found to be up-regulated via gene amplification or overexpression in breast cancers, hepatocellular carcinomas, squamous cell carcinomas, adrenocortical carcinomas, childhood medulloblastomas, and malignant pleural mesotheliomas. Because of its oncogenic activity in skin cancer and up-regulation in other malignancies, CUL4A has arisen as a potential candidate for targeted therapeutic approaches. In this review, we outline the established functions of CUL4A and discuss the E3 ligase’s emergence as a potential driver of tumorigenesis. Key words Ubiquitination, cullins, DNA damage, cell cycle regulation, skin cancer, therapeutic targets For most cellular proteins, stability and degradation are scaffold, and one or multiple substrate-recruiting proteins at the regulated by the ubiquitin-proteosome system in which proteins are N-terminus[1,2]. -
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. -
The Role of the C-Terminus Merlin in Its Tumor Suppressor Function Vinay Mandati
The role of the C-terminus Merlin in its tumor suppressor function Vinay Mandati To cite this version: Vinay Mandati. The role of the C-terminus Merlin in its tumor suppressor function. Agricultural sciences. Université Paris Sud - Paris XI, 2013. English. NNT : 2013PA112140. tel-01124131 HAL Id: tel-01124131 https://tel.archives-ouvertes.fr/tel-01124131 Submitted on 19 Mar 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 TABLE OF CONTENTS Abbreviations ……………………………………………………………………………...... 8 Resume …………………………………………………………………………………… 10 Abstract …………………………………………………………………………………….. 11 1. Introduction ………………………………………………………………………………12 1.1 Neurofibromatoses ……………………………………………………………………….14 1.2 NF2 disease ………………………………………………………………………………15 1.3 The NF2 gene …………………………………………………………………………….17 1.4 Mutational spectrum of NF2 gene ………………………………………………………..18 1.5 NF2 in other cancers ……………………………………………………………………...20 2. ERM proteins and Merlin ……………………………………………………………….21 2.1 ERMs ……………………………………………………………………………………..21 2.1.1 Band 4.1 Proteins and ERMs …………………………………………………………...21 2.1.2 ERMs structure ………………………………………………………………………....23 2.1.3 Sub-cellular localization and tissue distribution of ERMs ……………………………..25 2.1.4 ERM proteins and their binding partners ……………………………………………….25 2.1.5 Assimilation of ERMs into signaling pathways ………………………………………...26 2.1.5. A. ERMs and Ras signaling …………………………………………………...26 2.1.5. B. ERMs in membrane transport ………………………………………………29 2.1.6 ERM functions in metastasis …………………………………………………………...30 2.1.7 Regulation of ERM proteins activity …………………………………………………...31 2.1.7. -
Delineating the Role of Cooperativity in the Design of Potent Protacs for BTK
Delineating the role of cooperativity in the design of potent PROTACs for BTK Adelajda Zorbaa,b, Chuong Nguyenb, Yingrong Xub, Jeremy Starrb, Kris Borzillerib, James Smithb, Hongyao Zhuc, Kathleen A. Farleyb, WeiDong Dingb, James Schiemerb, Xidong Fengb, Jeanne S. Changb, Daniel P. Uccellob, Jennifer A. Youngb, Carmen N. Garcia-Irrizaryb, Lara Czabaniukb, Brandon Schuffb, Robert Oliverb, Justin Montgomeryb, Matthew M. Haywardb, Jotham Coeb, Jinshan Chenb, Mark Niosid, Suman Luthrae, Jaymin C. Shahe, Ayman El-Kattand, Xiayang Qiub, Graham M. Westb, Mark C. Noeb, Veerabahu Shanmugasundaramb, Adam M. Gilbertb, Matthew F. Brownb, and Matthew F. Calabreseb,1 aInternal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139; bDiscovery Sciences, Pfizer Worldwide Research and Development, Groton, CT 06340; cComputational Sciences, Medicinal Sciences, Pfizer Worldwide Research and Development, Groton, CT 06340; dMedicine Design, Pfizer Worldwide Research and Development, Groton, CT 06340; and ePharmaceutical Sciences Small Molecule, Pfizer Worldwide Research and Development, Cambridge, MA 02139 Edited by Vishva M. Dixit, Genentech, San Francisco, CA, and approved June 20, 2018 (received for review March 1, 2018) Proteolysis targeting chimeras (PROTACs) are heterobifunctional cellular compartments and for targets that have Lys residues small molecules that simultaneously bind to a target protein and accessible for ubiquitination. A second selection criterion en route an E3 ligase, thereby leading to ubiquitination and subsequent to efficacious and selective target degradation could be de novo degradation of the target. They present an exciting opportunity to rational design of PROTACs. In a recent report, Gadd et al. (18) modulate proteins in a manner independent of enzymatic or describe an elegant model of PROTAC-facilitated target–ligase signaling activity. -
Regulation of the Intranuclear Distribution of the Cockayne Syndrome Proteins Received: 26 July 2017 Teruaki Iyama, Mustafa N
www.nature.com/scientificreports OPEN Regulation of the Intranuclear Distribution of the Cockayne Syndrome Proteins Received: 26 July 2017 Teruaki Iyama, Mustafa N. Okur, Tyler Golato, Daniel R. McNeill, Huiming Lu , Accepted: 1 November 2018 Royce Hamilton, Aishwarya Raja, Vilhelm A. Bohr & David M. Wilson III Published: xx xx xxxx Cockayne syndrome (CS) is an inherited disorder that involves photosensitivity, developmental defects, progressive degeneration and characteristics of premature aging. Evidence indicates primarily nuclear roles for the major CS proteins, CSA and CSB, specifcally in DNA repair and RNA transcription. We reveal herein a complex regulation of CSB targeting that involves three major consensus signals: NLS1 (aa467-481), which directs nuclear and nucleolar localization in cooperation with NoLS1 (aa302-341), and NLS2 (aa1038-1055), which seemingly optimizes nuclear enrichment. CSB localization to the nucleolus was also found to be important for full UVC resistance. CSA, which does not contain any obvious targeting sequences, was adversely afected (i.e. presumably destabilized) by any form of truncation. No inter-coordination between the subnuclear localization of CSA and CSB was observed, implying that this aspect does not underlie the clinical features of CS. The E3 ubiquitin ligase binding partner of CSA, DDB1, played an important role in CSA stability (as well as DDB2), and facilitated CSA association with chromatin following UV irradiation; yet did not afect CSB chromatin binding. We also observed that initial recruitment of CSB to DNA interstrand crosslinks is similar in the nucleoplasm and nucleolus, although fnal accumulation is greater in the former. Whereas assembly of CSB at sites of DNA damage in the nucleolus was not afected by RNA polymerase I inhibition, stable retention at these sites of presumed repair was abrogated.