DOCSLIB.ORG

Diversity Roles of CHD1L in Normal Cell Function and Tumorigenesis Xifeng Xiong1† , Xudong Lai2†, Aiguo Li1*, Zhihe Liu1* and Ningfang Ma3,4*

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Diversity Roles of CHD1L in Normal Cell Function and Tumorigenesis Xifeng Xiong1† , Xudong Lai2†, Aiguo Li1*, Zhihe Liu1* and Ningfang Ma3,4* Xiong et al. Biomarker Research (2021) 9:16 https://doi.org/10.1186/s40364-021-00269-w REVIEW Open Access Diversity roles of CHD1L in normal cell function and tumorigenesis Xifeng Xiong1† , Xudong Lai2†, Aiguo Li1*, Zhihe Liu1* and Ningfang Ma3,4* Abstract Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a multifunctional protein participated in diverse cellular processes, including chromosome remodeling, cell differentiation and development. CHD1L is a regulator of chromosomal integrity maintenance, DNA repair and transcriptional regulation through its bindings to DNA. By regulating kinds of complex networks, CHD1L has been identified as a potent anti-apoptotic and pro- proliferative factor. CHD1L is also an oncoprotein since its overexpression leads to dysregulation of related downstream targets in various cancers. The latest advances in the functional molecular basis of CHD1L in normal cells will be described in this review. As the same time, we will describe the current understanding of CHD1L in terms of structure, characteristics, function and the molecular mechanisms underlying CHD1L in tumorigenesis. We inference that the role of CHD1L which involve in multiple cellular processes and oncogenesis is well worth further studying in basic biology and clinical relevance. Keywords: CHD1L, ALC1, SNF2, Chromatin remodeling, Tumorigenesis Introduction of nuclear activities, such as transcriptional inhibition or The CHD1L gene (Chromodomain helicase/ATPase activation, DNA recombination and repair [8, 9]. Like DNA binding protein 1-like gene), also called the ALC1 most SNF-like proteins, CHD1L is a regulator of gene (amplified in liver cancer 1), locates on chromo- chromosome integrity, transcriptional regulation and some 1q21 region of human hepatoma cells and is DNA repair through its bindings to DNA. The func- cloned by Guan using the comparative genomic tional diversity of CHD1L has always been related to the hybridization (CGH) technique [1–3]. Because CHD1L characteristics of helicases or chromatin remodeling en- has a consistent helicase sequence motif found in heli- zymes that interact with PAR and catalyze the sliding of case superfamily 2 proteins [1], it is classified as a su- nucleosomes stimulated by PAR polymerase 1 (PARP1) crose non-fermentation 2 like (SNF2-like) subfamily of [10, 11]. the SNF2 family [4–6]. Most SNF2-like proteins can CHD1L plays an important role as a transcription and utilize the energy, which is released from their DNA- translation activator of its target genes [1, 6, 12–19]. dependent ATPase activity, to stabilize or interfere with CHD1L can promote cell proliferation, enhance cell mi- protein-DNA interactions [7] and participate in a variety gration and inhibit apoptosis by regulating various com- plex networks [6, 12, 13]. For example, CHD1L is a well- known activator of ARHGEF9, TCTP, SPOCK1 and * Correspondence: [email protected]; [email protected]; – [email protected] NTKL [14 17] and can also lead to deregulation of p53, †Xifeng Xiong and Xudong Lai contributed equally to this work. TCTP and Nur77 [1, 15, 18]. Importantly, CHD1L 1 Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, shows carcinogenicity in the process of malignant trans- Jinan University, Guangzhou 510220, China 3Affiliated Cancer Hospital and Institute of Guangzhou Medical University, formation. CHD1L overexpression in cancer cells is Guangzhou 510095, China Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xiong et al. Biomarker Research (2021) 9:16 Page 2 of 18 considered as a biomarker of short tumor-free survival Characteristics and experssion pattern time and poor prognosis [12, 20–28]. CHD1L is a highly conserved gene among species in na- We will provide an overview of current understanding ture (https://www.ncbi.nlm.nih.gov/homologene/?term= about CHD1L on structure, characteristics, function and 11590). Human CHD1L is more than 87, 73, and 66% the molecular mechanisms underlying CHD1L in cancer similar to mammals, the less-evolved vertebrate chicken development in this review. As the same time, we will and zebrafish, respectively (Table 1). As conserved gene describe the latest development of CHD1L functions in in eukaryota (HomoloGene ID: 11590), CHD1L is in- normal cells. Finally, we will conclude that CHD1L is an volved in molecular function, cellular component, bio- attractively clinical target in the future molecular therapy logical process (Fig. 2a, Table 2)(http://www. of cancer. informatics.jax.org/homology/GOGraph/115 90#Annotations). Since CHD1L is expressed in many species including invertebrates, it appears that CHD1L Molecular and structural features of CHD1L exists in the common ancestor of vertebrates. In human, SNF2 superfamily CHD1L can be found in various tissues and exhibit dif- CHD1L protein belongs to the SNF2 superfamily pro- ferent expression patterns in space and time [22] (Fig. teins, which was identified by Ma [1]. The SNF2 super- 2b). For example, in the male reproductive system family proteins include ATP-dependent chromatin (testis), CHD1L is less expressed in mature cells than remodeling enzymes and play key roles in the progenitor cells [32, 33]. organization of genomic DNA in the natural chromatin state [7, 29]. The SNF2 superfamily proteins are further Biological function divided into ISWI (simulated switches), INO80 (inositol), Studies have described five spliced variants of the CHD (chromosomal domain helicase DNA binding) and CHD1L protein, and even found six spliced transcribed SWI/SNF (mating switch/non-sucrose fermentation) variants of the CHD1L gene [30]. Interestingly, CHD1L families [29]. In the mammalian, the ISWI family com- is a conserved protein with four conserved protein do- prises SNF2H and SNF2L. The SWI/SNF family proteins mains, namely SNF2_N domain, HELICc, SelS and contain brahma (BRM) and brahma-related gene 1 Macro domain (Fig. 1a). (BRG1). Based on the existence or nonexistence of add- SNF2_N domain is an important part of many proteins itional domains, the CHD family contains three subfam- that involved in a variety of cell biological processes in- ilies: Chd1-Chd2, Chd3-Chd4, and Chd5-Chd9 [29]. The cluding DNA repair, chromatin unwinding, DNA recom- CHD family has the characteristics of two signature se- bination, and transcription regulation, but also is quence motifs. One is the conserved SNF2_N domain at composed of some proteins with little functional infor- the N-terminal tandem chromodomain, and the other is mation [9, 34]. the SNF2-like ATPase domain at the center, also known HELICc is a component of multiple helicases and as the helicase superfamily c-terminal domain (HELICc) helicase-related proteins and DEAD-, DEXDc-, DEAH- [9]. The SNF2_N domains (containing 280 amino acids box associated proteins [35, 36], hepatitis C virus NS3, (aa)) of CHD1L and CHD1 have 45% identity, while ski2p and yeast initiation factor 4A [37]. The HELICc is their HELICc domains (containing 107 amino acids) not an autonomous folding unit, but is an essential part have 59% identity [1]. of the helicases that utilize the energy from nucleoside CHD1L is mapped to chromosome 1q21 [30]. The triphosphate hydrolysis to provide fuel for their trans- full-length messenger RNA of CHD1L (NM_004284.6) location along DNA and unwinding double-stranded contains 3036 base pairs with a presumptive open read- DNA in the process [36, 38]. The HELICc also contains ing frame encoding an 897 aa protein [1]. As shown in DEAD-like helicase superfamily (ATP-binding) region Fig. 1a, CHD1L mainly contains four domains: a con- which participates in ATP-dependent DNA or RNA served SNF2_N domains, a helicase superfamily domains unwinding. (HELICc), selenoprotein S (SelS) and a Macro domains SelS family contains several mammalian SelS se- [1]. The upstream of CHD1L gene is flavin containing quences. SelS is a disordered protein which has a seleno monooxygenase 5 (FMO5) gene, while the downstream sulfide bond (between Cys-174 and Sec-188) and a redox of which have a long intergenic non-coding RNA 624 potential (− 234 mV) [31]. SelS is an efficient reductase (LINC00624) and a prostaglandin reductase pseudo gene that can catalyze the reduction of hydrogen peroxide (LOC100130018) [30]. In addition, human CHD1L has a [39]. SelS also has the ability to resist hydrogen peroxide Selenoprotein S (SelS) region (579–695 aa), which is a inactivation and may have an evolutionary advantage plasma membrane protein that exists in many cell types compared to cysteine-containing peroxidases [40]. and tissues [31]. Schematic representation of human Macro domain is a high-affinity ADP-ribose binding CHD1L protein is shown in Fig. 1a. module, which exists in various proteins in the form of Xiong et al. Biomarker Research (2021) 9:16 Page 3 of 18 Fig. 1 (See legend on next page.) Xiong et al. Biomarker Research (2021) 9:16 Page 4 of 18 (See figure on previous page.) Fig. 1 Structural representation, transcriptional effects and regulatory pathways of CDH1L.
Load more

Recommended publications
  • Understanding the Impact of 1Q21.1 Copy Number Variant
    Understanding the impact of 1q21.1 copy number variant Article (Published Version) Havard, Chansonette, Strong, Emma, Mercier, Eloi, Colnaghi, Rita, Alcantara, Diana Rita Ralha, Chow, Eva, Martell, Sally, Tyson, Christine, Hrynchak, Monica, McGillivray, Barbara, Hamilton, Sara, Marles, Sandra, Mhanni, Aziz, Dawson, Angelika J, Pavlidis, Paul et al. (2011) Understanding the impact of 1q21.1 copy number variant. Orphanet Journal of Rare Diseases, 6 (54). pp. 1-12. ISSN 1750-1172 This version is available from Sussex Research Online: http://sro.sussex.ac.uk/id/eprint/41577/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the URL above for details on accessing the published version. Copyright and reuse: Sussex Research Online is a digital repository of the research output of the University. Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available. Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way.
    [Show full text]
  • PARSANA-DISSERTATION-2020.Pdf
    DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks.
    [Show full text]
  • The DNA Repair Inhibitor Dbait Is Specific for Malignant Hematologic Cells in Blood
    Author Manuscript Published OnlineFirst on September 25, 2017; DOI: 10.1158/1535-7163.MCT-17-0405 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. TITLE. The DNA repair inhibitor Dbait is specific for malignant hematologic cells in blood. Sylvain Thierry 1, Wael Jdey 1,2, Solana Alculumbre 3, Vassili Soumelis 3, Patricia Noguiez-Hellin 1, and Marie Dutreix 1*. 1 Institut Curie, PSL Research University, CNRS UMR 3347, INSERM U1021, Paris-Sud University, F- 91405, Orsay, France. 2 DNA-Therapeutics, Onxeo, F-75013 Paris, France 3 Institut Curie, PSL Research University, INSERM U932, F-75005 Paris, France *To whom correspondence should be addressed. Dr Marie Dutreix: Institut Curie, centre universitaire, bat110, F-91405 Orsay, France ; Tel: +33 1 69 86 71 86; Email: [email protected]; RUNNING TITLE. Toxicity and efficacy of Dbait on hematologic cells KEY WORDS. Dbait, AsiDNA, DNA repair inhibitor. FINANCIAL SUPPORT This work was supported by the SIRIC-Curie, the Institut Curie, the Centre National de la Recherche Scientifique, the Institut National de la Santé Et de la Recherche Médicale and the Agence Nationale de la Recherche. W. Jdey was supported by fellowship CIFFRE-ANRT (2013/0907). S. Thierry was supported by the Institut National du Cancer (TRANSLA13-081). Funding for open access charge: Institut Curie. 1 Downloaded from mct.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 25, 2017; DOI: 10.1158/1535-7163.MCT-17-0405 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • Genetic Screens in Isogenic Mammalian Cell Lines Without Single Cell Cloning
    ARTICLE https://doi.org/10.1038/s41467-020-14620-6 OPEN Genetic screens in isogenic mammalian cell lines without single cell cloning Peter C. DeWeirdt1,2, Annabel K. Sangree1,2, Ruth E. Hanna1,2, Kendall R. Sanson1,2, Mudra Hegde 1, Christine Strand 1, Nicole S. Persky1 & John G. Doench 1* Isogenic pairs of cell lines, which differ by a single genetic modification, are powerful tools for understanding gene function. Generating such pairs of mammalian cells, however, is labor- 1234567890():,; intensive, time-consuming, and, in some cell types, essentially impossible. Here, we present an approach to create isogenic pairs of cells that avoids single cell cloning, and screen these pairs with genome-wide CRISPR-Cas9 libraries to generate genetic interaction maps. We query the anti-apoptotic genes BCL2L1 and MCL1, and the DNA damage repair gene PARP1, identifying both expected and uncharacterized buffering and synthetic lethal interactions. Additionally, we compare acute CRISPR-based knockout, single cell clones, and small- molecule inhibition. We observe that, while the approaches provide largely overlapping information, differences emerge, highlighting an important consideration when employing genetic screens to identify and characterize potential drug targets. We anticipate that this methodology will be broadly useful to comprehensively study gene function across many contexts. 1 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA. 2These authors contributed equally: Peter C. DeWeirdt,
    [Show full text]
  • Mouse Spock1 Knockout Project (CRISPR/Cas9)
    https://www.alphaknockout.com Mouse Spock1 Knockout Project (CRISPR/Cas9) Objective: To create a Spock1 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Spock1 gene (NCBI Reference Sequence: NM_009262 ; Ensembl: ENSMUSG00000056222 ) is located on Mouse chromosome 13. 12 exons are identified, with the ATG start codon in exon 2 and the TAG stop codon in exon 12 (Transcript: ENSMUST00000185502). Exon 5 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for a targeted null mutation display no obvious morphological or behavioral abnormalities, are fertile, and have normal life spans. Adult homozygotes exhibit normal brain morphology and EEG recordings. Exon 5 starts from about 18.25% of the coding region. Exon 5 covers 8.67% of the coding region. The size of effective KO region: ~115 bp. The KO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele gRNA region 5' gRNA region 3' 1 5 12 Legends Exon of mouse Spock1 Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 5 is aligned with itself to determine if there are tandem repeats. Tandem repeats are found in the dot plot matrix. The gRNA site is selected outside of these tandem repeats.
    [Show full text]
  • Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated
    www.nature.com/scientificreports OPEN Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508 Received: 10 November 2017 Xia Hou1,2, Hongguang Wei1, Carthic Rajagopalan1, Hong Jiang1, Qingtian Wu2, Accepted: 6 March 2018 Khalequz Zaman3, Youming Xie4 & Fei Sun1 Published: xx xx xxxx Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important quality control mechanism that eliminates misfolded proteins from the ER. The Derlin-1/VCP/VIMP protein complex plays an essential role in ERAD. Although the roles of Derlin-1 and VCP are relatively clear, the functional activity of VIMP in ERAD remains to be understood. Here we investigate the role of VIMP in the degradation of CFTRΔF508, a cystic fbrosis transmembrane conductance regulator (CFTR) mutant known to be a substrate of ERAD. Overexpression of VIMP markedly enhances the degradation of CFTRΔF508, whereas knockdown of VIMP increases its half-life. We demonstrate that VIMP is associated with CFTRΔF508 and the RNF5 E3 ubiquitin ligase (also known as RMA1). Thus, VIMP not only forms a complex with Derlin-1 and VCP, but may also participate in recruiting substrates and E3 ubiquitin ligases. We further show that blocking CFTRΔF508 degradation by knockdown of VIMP substantially augments the efect of VX809, a drug that allows a fraction of CFTRΔF508 to fold properly and mobilize from ER to cell surface for normal functioning. This study provides insight into the role of VIMP in ERAD and presents a potential target for the treatment of cystic fbrosis patients carrying the CFTRΔF508 mutation. Elimination of misfolded endoplasmic reticulum (ER) proteins by the ER-associated protein degradation (ERAD) pathway is an important physiological adaptation to ER stress1,2.
    [Show full text]
  • Specificity Landscapes Unmask Submaximal Binding Site Preferences of Transcription Factors
    Specificity landscapes unmask submaximal binding site preferences of transcription factors Devesh Bhimsariaa,b,1, José A. Rodríguez-Martíneza,2, Junkun Panc, Daniel Rostonc, Elif Nihal Korkmazc, Qiang Cuic,3, Parameswaran Ramanathanb, and Aseem Z. Ansaria,d,4 aDepartment of Biochemistry, University of Wisconsin–Madison, Madison, WI 53706; bDepartment of Electrical and Computer Engineering, University of Wisconsin–Madison, Madison, WI 53706; cDepartment of Chemistry, University of Wisconsin–Madison, Madison, WI 53706; and dThe Genome Center of Wisconsin, University of Wisconsin–Madison, Madison, WI 53706 Edited by Michael Levine, Princeton University, Princeton, NJ, and approved September 24, 2018 (received for review July 13, 2018) We have developed Differential Specificity and Energy Landscape Here, we report the development of Differential Specificity (DiSEL) analysis to comprehensively compare DNA–protein inter- and Energy Landscapes (DiSEL) to compare experimental actomes (DPIs) obtained by high-throughput experimental plat- platforms, computational methods, and interactomes of TFs, forms and cutting edge computational methods. While high-affinity especially those factors that bind identical consensus motifs. Our DNA binding sites are identified by most methods, DiSEL uncovered results reveal that (i) most high-throughput experimental plat- nuanced sequence preferences displayed by homologous transcription forms reliably identify high-affinity motifs but yield less reliable factors. Pairwise analysis of 726 DPIs uncovered homolog-specific dif- information on submaximal sites; (ii) with few exceptions, com- ferences at moderate- to low-affinity binding sites (submaximal sites). putational methods model DPIs with a focus on high-affinity DiSEL analysis of variants of 41 transcription factors revealed that sites; (iii) submaximal sites improve the annotation of biologi- many disease-causing mutations result in allele-specific changes in cally relevant binding sites across genomes; (iv) among members binding site preferences.
    [Show full text]
  • Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Defi Cient Prostate Cancer
    Published OnlineFirst May 8, 2020; DOI: 10.1158/2159-8290.CD-19-1352 RESEARCH ARTICLE Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Defi cient Prostate Cancer Di Zhao 1 , 2 , Li Cai 1 , Xin Lu 1 , 3 , Xin Liang 1 , 4 , Jiexi Li 1 , Peiwen Chen 1 , Michael Ittmann 5 , Xiaoying Shang 1 , Shan Jiang6 , Haoyan Li 2 , Chenling Meng 2 , Ivonne Flores 6 , Jian H. Song 4 , James W. Horner 6 , Zhengdao Lan 1 , Chang-Jiun Wu6 , Jun Li 6 , Qing Chang 7 , Ko-Chien Chen 1 , Guocan Wang 1 , 4 , Pingna Deng 1 , Denise J. Spring 1 , Y. Alan Wang1 , and Ronald A. DePinho 1 Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 8, 2020; DOI: 10.1158/2159-8290.CD-19-1352 ABSTRACT Genetic inactivation of PTEN is common in prostate cancer and correlates with poorer prognosis. We previously identifi edCHD1 as an essential gene in PTEN- defi cient cancer cells. Here, we sought defi nitivein vivo genetic evidence for, and mechanistic under- standing of, the essential role of CHD1 in PTEN-defi cient prostate cancer. In Pten and Pten /Smad4 genetically engineered mouse models, prostate-specifi c deletion ofChd1 resulted in markedly delayed tumor progression and prolonged survival. Chd1 deletion was associated with profound tumor microenvironment (TME) remodeling characterized by reduced myeloid-derived suppressor cells (MDSC) and increased CD8+ T cells. Further analysis identifi ed IL6 as a key transcriptional target of CHD1, which plays a major role in recruitment of immunosuppressive MDSCs.
    [Show full text]
  • 1Q21.1 Duplication Syndrome and Epilepsy Case Report and Review
    CLINICAL/SCIENTIFIC NOTES OPEN ACCESS 1q21.1 Duplication syndrome and epilepsy Case report and review Ioulia Gourari, MD, Romaine Schubert, MD, and Aparna Prasad, PhD Correspondence Dr. Gourari Neurol Genet 2018;4:e219. doi:10.1212/NXG.0000000000000219 [email protected] Copy number variants (CNVs) of 1q21.1 are increasingly being recognized due to the wide- spread use of genetic screening tests for the investigation of developmental disorders and epilepsy. These include microdeletion and microduplication syndromes, associated with a wide variety of pathology including autism spectrum disorders, attention-deficit disorder, learning disabilities, hypotonia, facial dysmorphisms, and schizophrenia. The 1q21.1 region is consid- ered to be genetically unstable because it contains one of the largest areas of identical dupli- cation sequences in the human genome. Epilepsy has been reported in the literature, particularly in microdeletion syndromes, but rarely in association with microduplication syn- dromes. We report a patient with epilepsy and autism spectrum disorder due to a distal 1q21.1 microduplication and review the available literature and genetic information. Case report We present a 10-year-old girl with a low-functioning autism spectrum disorder and focal motor epilepsy. On examination, she has hypertelorism, minimal communicative language skills, and severe macrocephaly (HC = 57 cm, 3.6 SD > 99%). Seizures started at 7 years of age and consisted of head deviation to the left, generalized stiffening, clonic activity of the mouth, and fluttering of the eyelids, lasting for 1–2 minutes. Multiple video EEG recordings showed a right temporal focus with a less active, independent left temporal focus. 3T MRI scan of the brain was normal.
    [Show full text]
  • Asidna Is a Radiosensitizer with No Added Toxicity in Medulloblastoma
    Published OnlineFirst September 8, 2020; DOI: 10.1158/1078-0432.CCR-20-1729 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY AsiDNA Is a Radiosensitizer with no Added Toxicity in Medulloblastoma Pediatric Models Sofia Ferreira1,2, Chloe Foray1,2, Alberto Gatto3,4, Magalie Larcher1,2, Sophie Heinrich1,2, Mihaela Lupu5,6, Joel Mispelter5,6, Francois¸ D. Boussin7,Celio Pouponnot1,2, and Marie Dutreix1,2 ABSTRACT ◥ Purpose: Medulloblastoma is an important cause of mortality of medulloblastoma cell lines from different molecular subgroups and morbidity in pediatric oncology. Here, we investigated and TP53 status. Role of TP53 on the AsiDNA-mediated radio- whether the DNA repair inhibitor, AsiDNA, could help address sensitization was analyzed by RNA-sequencing, DNA repair asignificant unmet clinical need in medulloblastoma care, by recruitment, and cell death assays. improving radiotherapy efficacy without increasing radiation- Results: Capable of penetrating young brain tissues, AsiDNA associated toxicity. showed no added toxicity to radiation. Combination of AsiDNA Experimental Design: To evaluate the brain permeability of with radiotherapy improved the survival of animal models more AsiDNA upon systemic delivery, we intraperitoneally injected a efficiently than increasing radiation doses. Medulloblastoma radio- fluorescence form of AsiDNA in models harboring brain tumors sensitization by AsiDNA was not restricted to a specific molecular and in models still in development. Studies evaluated toxicity group or status of TP53. Molecular mechanisms of AsiDNA, associated with combination of AsiDNA with radiation in the previously observed in adult malignancies, were conserved in treatment of young developing animals at subacute levels, related pediatric models and resembled dose increase when combined with to growth and development, and at chronic levels, related to brain irradiation.
    [Show full text]
  • Asidna Is a Radiosensitizer with No Added Toxicity in Medulloblastoma Pediatric Models
    Author Manuscript Published OnlineFirst on September 8, 2020; DOI: 10.1158/1078-0432.CCR-20-1729 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. AsiDNA is a radiosensitizer with no added toxicity in medulloblastoma pediatric models Sofia Ferreira1,2, Chloe Foray1,2, Alberto Gatto3,4 Magalie Larcher1,2, Sophie Heinrich1,2, Mihaela Lupu5,6, Joel Mispelter5.6, Francois D. Boussin7, Celio Pouponnot1,2, Marie Dutreix1,2 * 1 Institut Curie, PSL Research University, CNRS UMR 3347, INSERM U1021, F-91405 Orsay, France. 2 Institut Curie, Université Paris-Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, F-91405 Orsay, France. 3 Institut Curie, Paris Sciences et Lettres Research University, Centre National de la Recherche Scientifique, UMR3664, Equipe Labellisée Ligue contre le Cancer, Paris, France. 4 Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Centre National de la Recherche Scientifique, UMR3664, Paris, France 5 Institut Curie, Research Center, PSL Research University, CNRS UMR 9187, INSERM U 1196, F-91405 Orsay, France. 6 Institut Curie, Université Paris-Sud, Université Paris-Saclay, CNRS UMR 9187, INSERM U1196, F-91405 Orsay, France 7 UMR Stabilité Génétique Cellules Souches et Radiations, Inserm, Université de Paris, Université Paris-Saclay, CEA, 18 route du Panorama 92265 Fontenay-aux Roses, France. Running title: AsiDNA to radiosensitize medulloblastoma * To whom correspondence should be addressed: Marie Dutreix, Institut Curie UMR3347. Université Paris-Sud, Building 112. 15, rue Georges Clémenceau – F-91405 Orsay, France. Tel: +33 1 69 86 71 86; Fax: +33 1 69 86 31 41; Email: [email protected].
    [Show full text]
  • The Chromatin Remodeling Factor CHD5 Is a Transcriptional Repressor of WEE1
    The Chromatin Remodeling Factor CHD5 Is a Transcriptional Repressor of WEE1 The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Quan, Jinhua, Guillaume Adelmant, Jarrod A. Marto, A. Thomas Look, and Timur Yusufzai. 2014. “The Chromatin Remodeling Factor CHD5 Is a Transcriptional Repressor of WEE1.” PLoS ONE 9 (9): e108066. doi:10.1371/journal.pone.0108066. http:// dx.doi.org/10.1371/journal.pone.0108066. Published Version doi:10.1371/journal.pone.0108066 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:13347631 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA The Chromatin Remodeling Factor CHD5 Is a Transcriptional Repressor of WEE1 Jinhua Quan1,2, Guillaume Adelmant2,3, Jarrod A. Marto2,3, A. Thomas Look4, Timur Yusufzai1,2* 1 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, 2 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America, 3 Blais Proteomics Center, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, 4 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America Abstract Loss of the chromatin remodeling ATPase CHD5 has been linked to the progression of neuroblastoma tumors, yet the underlying mechanisms behind the tumor suppressor role of CHD5 are unknown.
    [Show full text]