Gene Expression Responses to DNA Damage Are Altered in Human Aging and in Werner Syndrome
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A Ph-Eqtl Interaction at the RIT2-SYT4 Parkinson's Disease Risk
bioRxiv preprint doi: https://doi.org/10.1101/2020.12.16.423140; this version posted June 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A pH-eQTL interaction at the RIT2-SYT4 Parkinson’s disease risk locus in the substantia nigra Authors and affiliations: Sejal Patel1*, Derek Howard1, Leon French1,2,3,4* 1. Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada 2. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada 3. Department of Psychiatry, University of Toronto, Toronto 4. Institute for Medical Science, University of Toronto, Toronto, Canada Abstract Parkinson's disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson's disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. To assess these pH associations in relation to PD risk, we examined the two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain (n=100). Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. -
Nucleotide Excision Repair Gene ERCC2 and ERCC5 Variants Increase Risk of Uterine Cervical Cancer
pISSN 1598-2998, eISSN 2005-9256 Cancer Res Treat. 2016;48(2):708-714 http://dx.doi.org/10.4143/crt.2015.098 Original Article Open Access Nucleotide Excision Repair Gene ERCC2 and ERCC5 Variants Increase Risk of Uterine Cervical Cancer Jungnam Joo, PhD 1, Kyong-Ah Yoon, PhD 2, Tomonori Hayashi, PhD 3, Sun-Young Kong, MD, PhD 4, Hye-Jin Shin, MS 5, Boram Park, MS 1, Young Min Kim, PhD 6, Sang-Hyun Hwang, MD, PhD 7, Jeongseon Kim, PhD 8, Aesun Shin, MD, PhD 8,9 , Joo-Young Kim, MD, PhD 5,10 1Biometric Research Branch, 2Lung Cancer Branch, National Cancer Center, Goyang, Korea, 3Department of Radiobiology and Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan, 4Translational Epidemiology Research Branch and Department of Laboratory Medicine, 5Radiation Medicine Branch, National Cancer Center, Goyang, Korea, 6Department of Statistics, Radiation Effects Research Foundation, Hiroshima, Japan, 7Hematologic Malignancy Branch and Department of Laboratory Medicine, 8Molecular Epidemiology Branch, National Cancer Center, Goyang, 9Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 10 Center for Proton Therapy, Research Institute and Hospital, National Cancer Center, Goyang, Korea Supplementary Data Table of Contents Supplementary Fig. S1 ........................................................................................................................................................................... 2 Supplementary Table 1 ......................................................................................................................................................................... -
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CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders Michael F. Walsh1, Vivian Y. Chang2, Wendy K. Kohlmann3, Hamish S. Scott4, Christopher Cunniff5, Franck Bourdeaut6, Jan J. Molenaar7, Christopher C. Porter8, John T. Sandlund9, Sharon E. Plon10, Lisa L. Wang10, and Sharon A. Savage11 Abstract DNA repair syndromes are heterogeneous disorders caused by around the world to discuss and develop cancer surveillance pathogenic variants in genes encoding proteins key in DNA guidelines for children with cancer-prone disorders. Herein, replication and/or the cellular response to DNA damage. The we focus on the more common of the rare DNA repair dis- majority of these syndromes are inherited in an autosomal- orders: ataxia telangiectasia, Bloom syndrome, Fanconi ane- recessive manner, but autosomal-dominant and X-linked reces- mia, dyskeratosis congenita, Nijmegen breakage syndrome, sive disorders also exist. The clinical features of patients with DNA Rothmund–Thomson syndrome, and Xeroderma pigmento- repair syndromes are highly varied and dependent on the under- sum. Dedicated syndrome registries and a combination of lying genetic cause. Notably, all patients have elevated risks of basic science and clinical research have led to important in- syndrome-associated cancers, and many of these cancers present sights into the underlying biology of these disorders. Given the in childhood. Although it is clear that the risk of cancer is rarity of these disorders, it is recommended that centralized increased, there are limited data defining the true incidence of centers of excellence be involved directly or through consulta- cancer and almost no evidence-based approaches to cancer tion in caring for patients with heritable DNA repair syn- surveillance in patients with DNA repair disorders. -
Identification of Novel Pathogenic MSH2 Mutation and New DNA Repair Genes Variants: Investigation of a Tunisian Lynch Syndrome F
Jaballah‑Gabteni et al. J Transl Med (2019) 17:212 https://doi.org/10.1186/s12967‑019‑1961‑9 Journal of Translational Medicine RESEARCH Open Access Identifcation of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins Amira Jaballah‑Gabteni1,3* , Haifa Tounsi1,3, Maria Kabbage1,3, Yosr Hamdi3, Sahar Elouej3,4, Ines Ben Ayed1,3, Mouna Medhioub2, Moufda Mahmoudi2, Hamza Dallali3, Hamza Yaiche1,3, Nadia Ben Jemii1,3, Affa Maaloul1, Najla Mezghani1,3, Sonia Abdelhak3, Lamine Hamzaoui2, Mousaddak Azzouz2 and Samir Boubaker1,3 Abstract Background: Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome, characterized by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. Despite several genetic variations that have been identifed in various populations, the penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether, besides pathogenic mutations, environment and low penetrance genetic risk factors may result in phenotype modifcation in a Tunisian LS family. Patients and methods: A Tunisian family with strong colorectal cancer (CRC) history that fulfll the Amsterdam I criteria for the diagnosis of Lynch syndrome was proposed for oncogenetic counseling. The index case was a man, diagnosed at the age of 33 years with CRC. He has a monozygotic twin diagnosed at the age of 35 years with crohn disease. Forty‑seven years‑old was the onset age of his paternal uncle withCRC. An immunohistochemical (IHC) labe‑ ling for the four proteins (MLH1, MSH2, MSH6 and PMS2) of the MisMatchRepair (MMR) system was performed for the index case. -
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. -
Association of Smoking and XPG, CYP1A1, OGG1, ERCC5, ERCC1, MMP2, and MMP9 Gene Polymorphisms with the Early Detection and Occurrence of Laryngeal Squamous Carcinoma
Journal of Cancer 2018, Vol. 9 968 Ivyspring International Publisher Journal of Cancer 2018; 9(6): 968-977. doi: 10.7150/jca.22841 Research Paper Association of Smoking and XPG, CYP1A1, OGG1, ERCC5, ERCC1, MMP2, and MMP9 Gene Polymorphisms with the early detection and occurrence of Laryngeal Squamous Carcinoma Yi Zhu1, Luo Guo2, ShengZi Wang1,Qun Yu3, JianXiong Lu3 1. Department of Radiation Oncology of Shanghai Eye and ENT Hospital of Fudan University, Shanghai, 200031, China 2. Department of Experiment centre of Shanghai Eye and ENT Hospital of Fudan University, Shanghai,200031, China 3. Department of TianPing health service centre of Shanghai,Shanghai,200031,China Corresponding author: ShengZi Wang, Mail address: Department of Radiation Oncology of Shanghai, Eye and ENT Hospital of Fudan University, Shanghai 200031, China. Telephone: 8618917761761; Email: [email protected] © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2017.09.16; Accepted: 2018.01.16; Published: 2018.02.28 Abstract A total of 200 smoking-related laryngeal carcinoma patients with pathology confirmation from the Eye and ENT Hospital and 190 high-risk smokers were included in a survey. All of the participants had a smoking index greater than 400 (cigarettes/day*year.) We obtained data on clinical and baseline characteristics, and peripheral blood was obtained and subjected to DNA extraction to analyse the correlation between smoking and the occurrence of laryngeal carcinoma. We selected candidate genes and SNP fragments that were found to be closely associated with smoking-related tumours in preliminary studies. -
Zbtb16 Regulates Social Cognitive Behaviors and Neocortical
Usui et al. Translational Psychiatry (2021) 11:242 https://doi.org/10.1038/s41398-021-01358-y Translational Psychiatry ARTICLE Open Access Zbtb16 regulates social cognitive behaviors and neocortical development Noriyoshi Usui 1,2,3,4, Stefano Berto5,AmiKonishi1, Makoto Kondo1,4, Genevieve Konopka5,HideoMatsuzaki 2,6,7 and Shoichi Shimada1,2,4 Abstract Zinc finger and BTB domain containing 16 (ZBTB16) play the roles in the neural progenitor cell proliferation and neuronal differentiation during development, however, how the function of ZBTB16 is involved in brain function and behaviors unknown. Here we show the deletion of Zbtb16 in mice leads to social impairment, repetitive behaviors, risk- taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we conducted histological analyses and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia, as well as developmental defects in oligodendrocytes and neocortical myelination in the prefrontal cortex (PFC) of Zbtb16 KO mice. Using genomics approaches, we identified the Zbtb16 transcriptome that includes genes involved in neocortical maturation such as neurogenesis and myelination, and both autism spectrum disorder (ASD) and schizophrenia (SCZ) pathobiology. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ, respectively. Our study provides insight into the novel roles of ZBTB16 in behaviors and neocortical development related to the disorders. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction identified as a causative mutation for skeletal defects, ZBTB16 (PLZF) encodes a transcription factor, which genital hypoplasia, and mental retardation (SGYMR)6,7. -
Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle
animals Article Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle Masoumeh Naserkheil 1 , Abolfazl Bahrami 1 , Deukhwan Lee 2,* and Hossein Mehrban 3 1 Department of Animal Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj 77871-31587, Iran; [email protected] (M.N.); [email protected] (A.B.) 2 Department of Animal Life and Environment Sciences, Hankyong National University, Jungang-ro 327, Anseong-si, Gyeonggi-do 17579, Korea 3 Department of Animal Science, Shahrekord University, Shahrekord 88186-34141, Iran; [email protected] * Correspondence: [email protected]; Tel.: +82-31-670-5091 Received: 25 August 2020; Accepted: 6 October 2020; Published: 9 October 2020 Simple Summary: Hanwoo is an indigenous cattle breed in Korea and popular for meat production owing to its rapid growth and high-quality meat. Its yearling weight and carcass traits (backfat thickness, carcass weight, eye muscle area, and marbling score) are economically important for the selection of young and proven bulls. In recent decades, the advent of high throughput genotyping technologies has made it possible to perform genome-wide association studies (GWAS) for the detection of genomic regions associated with traits of economic interest in different species. In this study, we conducted a weighted single-step genome-wide association study which combines all genotypes, phenotypes and pedigree data in one step (ssGBLUP). It allows for the use of all SNPs simultaneously along with all phenotypes from genotyped and ungenotyped animals. Our results revealed 33 relevant genomic regions related to the traits of interest. -
TASOR Is a Pseudo-PARP That Directs HUSH Complex Assembly and Epigenetic Transposon Control
Lawrence Berkeley National Laboratory Recent Work Title TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control. Permalink https://escholarship.org/uc/item/6021r2cd Journal Nature communications, 11(1) ISSN 2041-1723 Authors Douse, Christopher H Tchasovnikarova, Iva A Timms, Richard T et al. Publication Date 2020-10-02 DOI 10.1038/s41467-020-18761-6 Peer reviewed eScholarship.org Powered by the California Digital Library University of California ARTICLE https://doi.org/10.1038/s41467-020-18761-6 OPEN TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control Christopher H. Douse 1,4,9, Iva A. Tchasovnikarova2,5,9, Richard T. Timms 2,9, Anna V. Protasio 2,6, Marta Seczynska2, Daniil M. Prigozhin 1,7, Anna Albecka1,2,8, Jane Wagstaff3, James C. Williamson2, ✉ ✉ Stefan M. V. Freund3, Paul J. Lehner 2 & Yorgo Modis 1,2 1234567890():,; The HUSH complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes. HUSH regulates deposition of the epigenetic mark H3K9me3, but how its three core subunits — TASOR, MPP8 and Periphilin — contribute to assembly and targeting of the complex remains unknown. Here, we define the biochemical basis of HUSH assembly and find that its modular architecture resembles the yeast RNA-induced tran- scriptional silencing complex. TASOR, the central HUSH subunit, associates with RNA pro- cessing components. TASOR is required for H3K9me3 deposition over LINE-1 repeats and repetitive exons in transcribed genes. In the context of previous studies, this suggests that an RNA intermediate is important for HUSH activity. We dissect the TASOR and MPP8 domains necessary for transgene repression. -
Fanconi Anemia, Bloom Syndrome and Breast Cancer
A multiprotein complex in DNA damage response network of Fanconi anemia, Bloom syndrome and Breast cancer Weidong Wang Lab of Genetics, NIA A Multi-protein Complex Connects Two Genomic Instability Diseases: Bloom Syndrome and Fanconi Anemia Bloom Syndrome . Genomic Instability: -sister-chromatid exchange . Cancer predisposition . Mutation in BLM, a RecQ DNA Helicase . BLM participates in: HR-dependent DSB repair Recovery of stalled replication forks . BLM works with Topo IIIa and RMI to Suppress crossover recombination Courtesy of Dr. Ian Hickson A Multi-protein Complex Connects Two Genomic Instability Diseases: Bloom Syndrome and Fanconi Anemia P I l o r t n o BLM IP kDa C HeLa BLAP 250 Nuclear Extract 200- BLM* FANCA* 116- TOPO IIIα* 97- BLAP 100 MLH1* BLM IP BLAP 75 * 66- RPA 70 IgG H 45- * 30- RPA32 IgG L 20- * 12- RPA14 Meetei et al. MCB 2003 A Multi-protein Complex Connects Two Genomic Instability Diseases: Bloom Syndrome and Fanconi Anemia P I A C N A F BLM IP HeLa FANCM= FAAP 250 BLAP 250 Nuclear Extract BLM* BLM* * FANCA* FANCA TOPO IIIα* TOPO IIIα* FAAP 100 BLAP 100 FANCB= FAAP 95 MLH1 FANCA IP BLM IP BLAP 75 BLAP 75 RPA70*/FANCG* RPA 70* FANCC*/FANCE* IgG H FANCL= FAAP 43 FANCF* RPA32* IgG L Meetei et al. MCB 2003 Meetei et al. Nat Genet. 2003, 2004, 2005 BRAFT-a Multisubunit Machine that Maintains Genome Stability and is defective in Fanconi anemia and Bloom syndrome BRAFT Super-complex Fanconi Anemia Bloom Syndrome Core Complex Complex 12 polypeptides 7 polypeptides FANCA BLM Helicase (HJ, fork, D-loop), fork FANCC regression, dHJ dissolution Topo IIIα Topoisomerase, FANCE dHJ dissolution FANCF BLAP75 RMI1 FANCG Stimulates dHJ dissolution. -
Co-Occupancy by Multiple Cardiac Transcription Factors Identifies
Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart Aibin Hea,b,1, Sek Won Konga,b,c,1, Qing Maa,b, and William T. Pua,b,2 aDepartment of Cardiology and cChildren’s Hospital Informatics Program, Children’s Hospital Boston, Boston, MA 02115; and bHarvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 Edited by Eric N. Olson, University of Texas Southwestern, Dallas, TX, and approved February 23, 2011 (received for review November 12, 2010) Identification of genomic regions that control tissue-specific gene study of a handful of model genes (e.g., refs. 7–10), it has not been expression is currently problematic. ChIP and high-throughput se- evaluated using unbiased, genome-wide approaches. quencing (ChIP-seq) of enhancer-associated proteins such as p300 In this study, we used a modified ChIP-seq approach to define identifies some but not all enhancers active in a tissue. Here we genome wide the binding sites of these cardiac TFs (1). We show that co-occupancy of a chromatin region by multiple tran- provide unbiased support for collaborative TF interactions in scription factors (TFs) identifies a distinct set of enhancers. GATA- driving cardiac gene expression and use this principle to show that chromatin co-occupancy by multiple TFs identifies enhancers binding protein 4 (GATA4), NK2 transcription factor-related, lo- with cardiac activity in vivo. The majority of these multiple TF- cus 5 (NKX2-5), T-box 5 (TBX5), serum response factor (SRF), and “ binding loci (MTL) enhancers were distinct from p300-bound myocyte-enhancer factor 2A (MEF2A), here referred to as cardiac enhancers in location and functional properties. -
Human XPG Nuclease Structure, Assembly, and Activities with Insights for Neurodegeneration and Cancer from Pathogenic Mutations
Human XPG nuclease structure, assembly, and activities with insights for neurodegeneration and cancer from pathogenic mutations Susan E. Tsutakawaa,1,2, Altaf H. Sarkerb,1, Clifford Ngb, Andrew S. Arvaic, David S. Shina, Brian Shihb, Shuai Jiangb, Aye C. Thwinb, Miaw-Sheue Tsaib, Alexandra Willcoxd,3, Mai Zong Hera, Kelly S. Tregob, Alan G. Raetzb,4, Daniel Rosenberga, Albino Bacollae,f, Michal Hammela, Jack D. Griffithd,2, Priscilla K. Cooperb,2, and John A. Tainera,e,f,2 aMolecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; bBiological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; cIntegrative Structural & Computational Biology, The Scripps Research Institute, La Jolla, CA 92037; dLineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 eDepartment of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and fDepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 Contributed by Jack D. Griffith, March 19, 2020 (sent for review December 9, 2019; reviewed by Alan R. Lehmann, Wim Vermeulen, and Scott Williams) Xeroderma pigmentosum group G (XPG) protein is both a func- containing an unpaired bubble (bubble DNA) through its direct tional partner in multiple DNA damage responses (DDR) and a interactions with TFIIH, the XPD helicase activity of which is pathway coordinator and structure-specific endonuclease in nucle- strongly stimulated by the interaction (2). Requiring the phys- otide excision repair (NER). Different mutations in the XPG gene ical presence of XPG, the XPF-ERCC1 heterodimer is ERCC5 lead to either of two distinct human diseases: Cancer-prone recruited and incises the double-stranded (ds)DNA 5′ to the xeroderma pigmentosum (XP-G) or the fatal neurodevelopmental lesion (3–6).