1,286 results match your criteria Cockayne Syndrome


Early-onset Nucleotide Excision Repair disorders with neurological impairment: clues for early diagnosis and prognostic counselling.

Clin Genet 2020 Jun 17. Epub 2020 Jun 17.

Laboratoires de Diagnostic Génétique, Institut de génétique médicale d'Alsace, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, France.

Nucleotide Excision Repair associated diseases comprise overlapping phenotypes and a wide range of outcomes. The early stages still remain under-investigated and underdiagnosed, even though an early recognition of the first symptoms is of utmost importance for appropriate care and genetic counselling. We systematically collected clinical and molecular data from the literature and from newly diagnosed NER patients with neurological impairment, presenting clinical symptoms before the age of 12 months, including foetal cases. Read More

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http://dx.doi.org/10.1111/cge.13798DOI Listing

Human XPG nuclease structure, assembly, and activities with insights for neurodegeneration and cancer from pathogenic mutations.

Proc Natl Acad Sci U S A 2020 Jun 10;117(25):14127-14138. Epub 2020 Jun 10.

Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720;

Xeroderma pigmentosum group G (XPG) protein is both a functional partner in multiple DNA damage responses (DDR) and a pathway coordinator and structure-specific endonuclease in nucleotide excision repair (NER). Different mutations in the XPG gene lead to either of two distinct human diseases: Cancer-prone xeroderma pigmentosum (XP-G) or the fatal neurodevelopmental disorder Cockayne syndrome (XP-G/CS). To address the enigmatic structural mechanism for these differing disease phenotypes and for XPG's role in multiple DDRs, here we determined the crystal structure of human XPG catalytic domain (XPGcat), revealing XPG-specific features for its activities and regulation. Read More

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http://dx.doi.org/10.1073/pnas.1921311117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321962PMC

Cockayne Syndrome: The many challenges and approaches to understand a multifaceted disease.

Genet Mol Biol 2020 20;43(1 suppl. 1):e20190085. Epub 2020 May 20.

Universidade Federal de Ouro Preto, Instituto de Ciências Exatas e Biológicas, Núcleo de Pesquisa em Ciências Biológicas & Departamento de Ciências Biológicas, Ouro Preto, MG, Brazil.

The striking and complex phenotype of Cockayne syndrome (CS) patients combines progeria-like features with developmental deficits. Since the establishment of the in vitro culture of skin fibroblasts derived from patients with CS in the 1970s, significant progress has been made in the understanding of the genetic alterations associated with the disease and their impact on molecular, cellular, and organismal functions. In this review, we provide a historic perspective on the research into CS by revisiting seminal papers in this field. Read More

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http://dx.doi.org/10.1590/1678-4685-GMB-2019-0085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250278PMC

Malar rash in a young child with neurodevelopmental delay: a quiz.

Arch Dis Child Educ Pract Ed 2020 May 23. Epub 2020 May 23.

Dermatology, American University of Beirut Medical Center, Beirut, Lebanon

-A 14-month-old boy born to consanguineous parents presented to our Dermatology Department with a 6-month history of a malar eczematous rash that worsens with sun exposure. He had butterfly-shaped, hyperpigmented exfoliating plaques, preceded by blister formation (figure 1). He was also noticed to have enophthalmos, a pinched nose, microcephaly and a cachectic physique. Read More

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http://dx.doi.org/10.1136/archdischild-2019-318334DOI Listing

The molecular genetics of cellular senescence in the context of organismal aging.

Cas Lek Cesk 2020 ;159(2):88-92

Cellular senescence is a physiological state generally defined as a stable arrest of proliferation by preventing the cells from cycling. Unlike terminally differentiated cells, that also do not show proliferative activity, cellular senescence is stress induced and blocks the proliferation of cells with theoretical ability to divide (such as progenitor, stem or cancer cells) due to the activity of specific signaling pathways. The number of senescent cells increases during the ontogenesis of an organism. Read More

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January 2020

[Anesthesia for a cesarean section on a pregnant patient with Cockayne syndrome: case report].

Rev Bras Anestesiol 2020 Jan - Feb;70(1):51-54. Epub 2020 Feb 19.

Universidade Federal Fluminense (UFF), Hospital Universitário Antônio Pedro, Niterói, RJ, Brasil. Electronic address:

Cockayne syndrome is an autosomal recessive multi-systemic disorder due to DNA repair failure. It was originally described in 1936 in children of small stature, retinal atrophy and deafness, characterized by dwarfism, cachexia, photosensitivity, premature aging and neurologic deficits. The most typical feature is described as birdlike facies: protruding maxilla, facial lipoatrophy, sunken eyes, large ears and thin nose. Read More

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http://dx.doi.org/10.1016/j.bjan.2019.10.002DOI Listing
February 2020

Atypical features and de novo heterozygous mutations in two siblings with Cockayne syndrome.

Mol Genet Genomic Med 2020 May 11;8(5):e1204. Epub 2020 Mar 11.

Children's Hospital of Soochow University, Suzhou, Jiangsu, China.

Background: Cockayne syndrome (CS) is a rare autosomal recessive disorder which displays multiorgan dysfunction, especially within the nervous system including psychomotor retardation, cerebral atrophy, microcephaly, cognitive dysfunction, mental retardation, and seizures. Many genetic variations reported were related to this syndrome, but splicing mutations with cardiac anomalies have not been found in previous studies.

Methods: Herein, we described a pair of brothers and sisters who present essential manifestations of CS including premature feature, developmental delay, growth failure, microcephaly, and characteristic facial features, such as sunken eyes and a beaked nose. Read More

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http://dx.doi.org/10.1002/mgg3.1204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216809PMC

Regulation of the RNAPII Pool Is Integral to the DNA Damage Response.

Cell 2020 Mar 5;180(6):1245-1261.e21. Epub 2020 Mar 5.

Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:

In response to transcription-blocking DNA damage, cells orchestrate a multi-pronged reaction, involving transcription-coupled DNA repair, degradation of RNA polymerase II (RNAPII), and genome-wide transcription shutdown. Here, we provide insight into how these responses are connected by the finding that ubiquitylation of RNAPII itself, at a single lysine (RPB1 K), is the focal point for DNA-damage-response coordination. K ubiquitylation affects DNA repair and signals RNAPII degradation, essential for surviving genotoxic insult. Read More

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http://dx.doi.org/10.1016/j.cell.2020.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103762PMC

Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair.

Cell 2020 Mar 5;180(6):1228-1244.e24. Epub 2020 Mar 5.

Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan; Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Transcription-coupled nucleotide excision repair (TC-NER) is initiated by the stalling of elongating RNA polymerase II (RNAPIIo) at DNA lesions. The ubiquitination of RNAPIIo in response to DNA damage is an evolutionarily conserved event, but its function in mammals is unknown. Here, we identified a single DNA damage-induced ubiquitination site in RNAPII at RPB1-K1268, which regulates transcription recovery and DNA damage resistance. Read More

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http://dx.doi.org/10.1016/j.cell.2020.02.010DOI Listing

Hepatic Failure following Metronidazole in Children with Cockayne Syndrome.

Case Rep Pediatr 2020 29;2020:9634196. Epub 2020 Jan 29.

Pediatric Gastroenterology and Hepatology Research Center, Tehran University of Medical Sciences, Department of Pediatric, Bahrami Children's Hospital, Tehran, Iran.

Cockayne syndrome is an uncommon autosomal recessive disease characterized by microcephaly, abnormal growth, and pathologic premature aging. The purpose of this report is to evaluate liver failure in children with Cockayne syndrome following metronidazole administration. The first case was a 2-year-old boy with Cockayne syndrome. Read More

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http://dx.doi.org/10.1155/2020/9634196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008298PMC
January 2020

The past, present, and future of modeling Cockayne Syndrome - A commentary on "Rat Model of Cockayne Syndrome Neurological Disease".

DNA Repair (Amst) 2020 04 28;88:102788. Epub 2020 Jan 28.

Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, and Office of Rare Disease Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.

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http://dx.doi.org/10.1016/j.dnarep.2020.102788DOI Listing

Multimodal imaging in a family with Cockayne syndrome with a novel pathogenic mutation in the ERCC8 gene, and significant phenotypic variability.

Doc Ophthalmol 2020 Feb 11. Epub 2020 Feb 11.

Loma Linda University Eye Institute, Loma Linda, CA, USA.

Background: Cockayne syndrome is a rare autosomal recessive neurodegenerative disorder caused by mutations of either the ERCC6/CSB or ERCC8/CSA genes. Here, we describe two sisters with Cockayne syndrome caused by compound heterozygous mutations in the ERCC8 gene using multimodal imaging. Significant ophthalmic and systemic phenotypic variability is discussed. Read More

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http://dx.doi.org/10.1007/s10633-020-09754-3DOI Listing
February 2020

Defective transcription of ATF3 responsive genes, a marker for Cockayne Syndrome.

Sci Rep 2020 Jan 24;10(1):1105. Epub 2020 Jan 24.

IGBMC, Department of Functional Genomics and Cancer, Equipe Labellisée Ligue 2014, CNRS/INSERM/University of Strasbourg, BP 163, 67404 Illkirch Cedex, C.U., Strasbourg, France.

Cockayne syndrome (CS) is a rare genetic disorder caused by mutations (dysfunction) in CSA and CSB. CS patients exhibit mild photosensitivity and severe neurological problems. Currently, CS diagnosis is based on the inefficiency of CS cells to recover RNA synthesis upon genotoxic (UV) stress. Read More

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http://dx.doi.org/10.1038/s41598-020-57999-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981198PMC
January 2020

CSB cooperates with SMARCAL1 to maintain telomere stability in ALT cells.

J Cell Sci 2020 Feb 17;133(4). Epub 2020 Feb 17.

Department of Biology, McMaster University, Hamilton, Ontario, Canada L8S 4K1

Elevated replication stress is evident at telomeres of about 10-15% of cancer cells, which maintain their telomeres via a homologous recombination (HR)-based mechanism, referred to as alternative lengthening of telomeres (ALT). How ALT cells resolve replication stress to support their growth remains incompletely characterized. Here, we report that CSB (also known as ERCC6) promotes recruitment of HR repair proteins (MRN, BRCA1, BLM and RPA32) and POLD3 to ALT telomeres, a process that requires the ATPase activity of CSB and is controlled by ATM- and CDK2-dependent phosphorylation. Read More

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http://dx.doi.org/10.1242/jcs.234914DOI Listing
February 2020

Cockayne syndrome group A and B proteins function in rRNA transcription through nucleolin regulation.

Nucleic Acids Res 2020 03;48(5):2473-2485

Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.

Cockayne Syndrome (CS) is a rare neurodegenerative disease characterized by short stature, accelerated aging and short lifespan. Mutations in two human genes, ERCC8/CSA and ERCC6/CSB, are causative for CS and their protein products, CSA and CSB, while structurally unrelated, play roles in DNA repair and other aspects of DNA metabolism in human cells. Many clinical and molecular features of CS remain poorly understood, and it was observed that CSA and CSB regulate transcription of ribosomal DNA (rDNA) genes and ribosome biogenesis. Read More

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http://dx.doi.org/10.1093/nar/gkz1242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049711PMC

as a Model Organism to Understand the Effects during Development of TFIIH-Related Human Diseases.

Int J Mol Sci 2020 Jan 17;21(2). Epub 2020 Jan 17.

Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca Morelos 62250, Mexico.

Human mutations in the transcription and nucleotide excision repair (NER) factor TFIIH are linked with three human syndromes: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS). In particular, different mutations in the XPB, XPD and p8 subunits of TFIIH may cause one or a combination of these syndromes, and some of these mutations are also related to cancer. The participation of TFIIH in NER and transcription makes it difficult to interpret the different manifestations observed in patients, particularly since some of these phenotypes may be related to problems during development. Read More

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http://dx.doi.org/10.3390/ijms21020630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013941PMC
January 2020

Short-term NAD supplementation prevents hearing loss in mouse models of Cockayne syndrome.

NPJ Aging Mech Dis 2020 7;6. Epub 2020 Jan 7.

1Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224 USA.

Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hearing loss at a young age, but is otherwise similar to ARHL. Read More

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http://dx.doi.org/10.1038/s41514-019-0040-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946667PMC
January 2020

CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence.

Nat Commun 2019 12 6;10(1):5576. Epub 2019 Dec 6.

Institut Pasteur, Stem Cells and Development, Department of Developmental and Stem Cell Biology, 75015, Paris, France.

Cellular senescence has causative links with ageing and age-related diseases, however, it remains unclear if progeroid factors cause senescence in normal cells. Here, we show that depletion of CSB, a protein mutated in progeroid Cockayne syndrome (CS), is the earliest known trigger of p21-dependent replicative senescence. CSB depletion promotes overexpression of the HTRA3 protease resulting in mitochondrial impairments, which are causally linked to CS pathological phenotypes. Read More

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http://dx.doi.org/10.1038/s41467-019-13314-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898346PMC
December 2019

USP7-mediated deubiquitination differentially regulates CSB but not UVSSA upon UV radiation-induced DNA damage.

Cell Cycle 2020 01 27;19(1):124-141. Epub 2019 Nov 27.

Department of Radiology, The Ohio State University College of Medicine, Columbus, OH, USA.

Cockayne syndrome group B (CSB) protein participates in transcription-coupled nucleotide excision repair. The stability of CSB is known to be regulated by ubiquitin-specific protease 7 (USP7). Yet, whether USP7 acts as a deubiquitinating enzyme for CSB is not clear. Read More

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http://dx.doi.org/10.1080/15384101.2019.1695996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927731PMC
January 2020

Transcription-coupled nucleotide excision repair is coordinated by ubiquitin and SUMO in response to ultraviolet irradiation.

Nucleic Acids Res 2020 01;48(1):231-248

Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, Leiden 2333 ZC, The Netherlands.

Cockayne Syndrome (CS) is a severe neurodegenerative and premature aging autosomal-recessive disease, caused by inherited defects in the CSA and CSB genes, leading to defects in transcription-coupled nucleotide excision repair (TC-NER) and consequently hypersensitivity to ultraviolet (UV) irradiation. TC-NER is initiated by lesion-stalled RNA polymerase II, which stabilizes the interaction with the SNF2/SWI2 ATPase CSB to facilitate recruitment of the CSA E3 Cullin ubiquitin ligase complex. However, the precise biochemical connections between CSA and CSB are unknown. Read More

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http://dx.doi.org/10.1093/nar/gkz977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145520PMC
January 2020

Adult diagnosis of Cockayne syndrome.

Neurology 2019 11;93(19):854-855

From the Department of Neurology (A.C., D.C., A.A.), IRCCS Humanitas Research Hospital and University, Rozzano, Milan; Department of Neuroscience (M.C.), University of Padua; Medical Genetics and Neurogenetics Unit (B.G.), IRCCS Carlo Besta Neurological Institute; and Department of Neurology (A.A.), Catholic University, Milan, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000008449DOI Listing
November 2019

Nucleotide excision repair genes shaping embryonic development.

Open Biol 2019 10 30;9(10):190166. Epub 2019 Oct 30.

Department of Chemistry, Faculty of Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.

Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA lesions. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human disorders caused by inherited defects in NER. Read More

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http://dx.doi.org/10.1098/rsob.190166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833223PMC
October 2019

DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering.

Nat Commun 2019 10 25;10(1):4887. Epub 2019 Oct 25.

Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.

Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. Read More

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http://dx.doi.org/10.1038/s41467-019-12640-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814737PMC
October 2019

Rat Model of Cockayne Syndrome Neurological Disease.

Cell Rep 2019 10;29(4):800-809.e5

Key Laboratory of Neurological Function and Health, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China. Electronic address:

Cockayne syndrome (CS) is a rare genetic neurodevelopmental disorder, characterized by a deficiency in transcription-coupled subpathway of nucleotide excision DNA repair (TC-NER). Mutation of the Cockayne syndrome B (CSB) gene affects basal transcription, which is considered a major cause of CS neurologic dysfunction. Here, we generate a rat model by mimicking a nonsense mutation in the CSB gene. Read More

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http://dx.doi.org/10.1016/j.celrep.2019.09.028DOI Listing
October 2019

, which lacks canonical transcription-coupled repair proteins, performs transcription-coupled repair.

J Biol Chem 2019 11 17;294(48):18092-18098. Epub 2019 Oct 17.

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, North Carolina 27599

Previous work with the classic T4 endonuclease V digestion of DNA from irradiated cells followed by Southern hybridization led to the conclusion that lacks transcription-coupled repair (TCR). This conclusion was reinforced by the Genome Project, which revealed that lacks Cockayne syndrome WD repeat protein (CSA), CSB, or UV-stimulated scaffold protein A (UVSSA) homologs, whose orthologs are present in eukaryotes ranging from to humans that carry out TCR. A recently developed excision assay and the excision repair-sequencing (XR-Seq) method have enabled genome-wide analysis of nucleotide excision repair in various organisms at single-nucleotide resolution and in a strand-specific manner. Read More

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http://dx.doi.org/10.1074/jbc.AC119.011448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885609PMC
November 2019

CSB affected on the sensitivity of lung cancer cells to platinum-based drugs through the global decrease of let-7 and miR-29.

BMC Cancer 2019 Oct 15;19(1):948. Epub 2019 Oct 15.

Institute of Molecular Genetics, College of Life Science, North China University of Science and Technology, Tangshan, China.

Background: Transcription-coupled nucleotide excision repair (TC-NER) plays a prominent role in the removal of DNA adducts induced by platinum-based chemotherapy reagents. Cockayne syndrome protein B (CSB), the master sensor of TCR, is also involved in the platinum resistant. Let-7 and miR-29 binding sites are highly conserved in the proximal 3'UTR of CSB. Read More

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http://dx.doi.org/10.1186/s12885-019-6194-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792260PMC
October 2019
1 Read

Two heterozygous mutations in the gene associated with Cockayne syndrome in a Chinese patient.

J Int Med Res 2019 Sep 26:300060519877997. Epub 2019 Sep 26.

Centre for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.

Objective: To confirm diagnosis and explore the genetic aetiology in a Chinese patient suspected to have Cockayne syndrome (CS).

Methods: The patient was clinically examined, and the patient and her biological parents underwent genetic analysis using whole exome sequencing (WES) and Sanger sequencing. The foetus of the patient's mother underwent prenatal diagnostic Sanger sequencing using amniotic fluid obtained at 19 weeks' gestation. Read More

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http://dx.doi.org/10.1177/0300060519877997DOI Listing
September 2019
1 Read

Multisystem analyses of two Cockayne syndrome associated proteins CSA and CSB reveal shared and unique functions.

DNA Repair (Amst) 2019 11 12;83:102696. Epub 2019 Sep 12.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China; School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China. Electronic address:

Mutations in the CSA and CSB genes are causative of Cockayne syndrome neurological disorder. Since the identification of indispensable functions of these two proteins in transcription-coupled repair and restoring RNA synthesis following DNA damage, the paradoxical less severe clinical symptoms reported in some CS-A patients have been puzzling. In this study we compared the effects of a CSA or a CSB defect at the levels of the cell and the intact organism. Read More

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http://dx.doi.org/10.1016/j.dnarep.2019.102696DOI Listing
November 2019

CSB modulates the competition between HIF-1 and p53 upon hypoxia.

Math Biosci Eng 2019 06;16(5):5247-5262

National Laboratory of Solid State Microstructures, Department of Physics, and Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, P.R. China.

Both hypoxia-inducible factor-1 (HIF-1) and tumor suppressor p53 are involved in the cellular response to hypoxia. It has been reported that HIF-1α induces cockayne syndrome B (CSB) to compete with p53 for limited p300. We developed a network model to clarify how the interplay between HIF-1 and p53 modulates cellular output in the presence of CSB. Read More

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http://dx.doi.org/10.3934/mbe.2019262DOI Listing

Signaling Pathways, Chemical and Biological Modulators of Nucleotide Excision Repair: The Faithful Shield against UV Genotoxicity.

Oxid Med Cell Longev 2019 7;2019:4654206. Epub 2019 Aug 7.

Univ. Grenoble Alpes, SYMMES/CIBEST UMR 5819 UGA-CNRS-CEA, INAC/CEA-Grenoble, Grenoble, France.

The continuous exposure of the human body's cells to radiation and genotoxic stresses leads to the accumulation of DNA lesions. Fortunately, our body has several effective repair mechanisms, among which is nucleotide excision repair (NER), to counteract these lesions. NER includes both global genome repair (GG-NER) and transcription-coupled repair (TC-NER). Read More

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http://dx.doi.org/10.1155/2019/4654206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702832PMC
February 2020
2 Reads

ERCC1-XPF targeting to psoralen-DNA crosslinks depends on XPA and FANCD2.

Cell Mol Life Sci 2020 May 7;77(10):2005-2016. Epub 2019 Aug 7.

Department of Molecular Genetics, Erasmus MC, 3015 GE, Rotterdam, The Netherlands.

The effectiveness of many DNA-damaging chemotherapeutic drugs depends on their ability to form monoadducts, intrastrand crosslinks and/or interstrand crosslinks (ICLs) that interfere with transcription and replication. The ERCC1-XPF endonuclease plays a critical role in removal of these lesions by incising DNA either as part of nucleotide excision repair (NER) or interstrand crosslink repair (ICLR). Engagement of ERCC1-XPF in NER is well characterized and is facilitated by binding to the XPA protein. Read More

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http://dx.doi.org/10.1007/s00018-019-03264-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228994PMC
May 2020
3 Reads

XPD/ERCC2 mutations interfere in cellular responses to oxidative stress.

Mutagenesis 2019 12;34(4):341-354

Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.

Nucleotide excision repair (NER) is a conserved, flexible mechanism responsible for the removal of bulky, helix-distorting DNA lesions, like ultraviolet damage or cisplatin adducts, but its role in the repair of lesions generated by oxidative stress is still not clear. The helicase XPD/ERCC2, one of the two helicases of the transcription complex IIH, together with XPB, participates both in NER and in RNA pol II-driven transcription. In this work, we investigated the responses of distinct XPD-mutated cell lines to the oxidative stress generated by photoactivated methylene blue (MB) and KBrO3 treatments. Read More

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http://dx.doi.org/10.1093/mutage/gez020DOI Listing
December 2019
5 Reads

Pre-existing H4K16ac levels in euchromatin drive DNA repair by homologous recombination in S-phase.

Commun Biol 2019 5;2:253. Epub 2019 Jul 5.

1Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030 USA.

The homologous recombination (HR) repair pathway maintains genetic integrity after DNA double-strand break (DSB) damage and is particularly crucial for maintaining fidelity of expressed genes. Histone H4 acetylation on lysine 16 (H4K16ac) is associated with transcription, but how pre-existing H4K16ac directly affects DSB repair is not known. To answer this question, we used CRISPR/Cas9 technology to introduce I-SceI sites, or repair pathway reporter cassettes, at defined locations within gene-rich (high H4K16ac/euchromatin) and gene-poor (low H4K16ac/heterochromatin) regions. Read More

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http://dx.doi.org/10.1038/s42003-019-0498-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611875PMC
May 2020
3 Reads

Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging.

Nucleic Acids Res 2019 09;47(16):8548-8562

Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.

Cockayne syndrome is an accelerated aging disorder, caused by mutations in the CSA or CSB genes. In CSB-deficient cells, poly (ADP ribose) polymerase (PARP) is persistently activated by unrepaired DNA damage and consumes and depletes cellular nicotinamide adenine dinucleotide, which leads to mitochondrial dysfunction. Here, the distribution of poly (ADP ribose) (PAR) was determined in CSB-deficient cells using ADPr-ChAP (ADP ribose-chromatin affinity purification), and the results show striking enrichment of PAR at transcription start sites, depletion of heterochromatin and downregulation of H3K9me3-specific methyltransferases SUV39H1 and SETDB1. Read More

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http://dx.doi.org/10.1093/nar/gkz568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895253PMC
September 2019

Basal ganglia calcifications (Fahr's syndrome): related conditions and clinical features.

Neurol Sci 2019 Nov 2;40(11):2251-2263. Epub 2019 Jul 2.

Department "GF Ingrassia", Section Neuroscience, University of Catania, Via Santa Sofia 78, 95123, Catania, Italy.

Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms associated with bilateral basal ganglia calcifications (which could occur in other peculiar brain structures, such as dentate nuclei) identifies a clinical picture defined as Fahr's Disease. This denomination mainly refers to idiopathic forms in which no metabolic or other underlying causes are identified. Read More

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http://dx.doi.org/10.1007/s10072-019-03998-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817747PMC
November 2019
3 Reads

Joining the hidden revolution in rare diseases: working with family support groups.

Arch Dis Child 2020 02 13;105(2):107-108. Epub 2019 Jun 13.

Amy and Friends Cockayne Syndrome Support, Wirral, UK.

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http://dx.doi.org/10.1136/archdischild-2019-317227DOI Listing
February 2020
2 Reads

Nucleolar and Ribosomal Dysfunction-A Common Pathomechanism in Childhood Progerias?

Cells 2019 06 4;8(6). Epub 2019 Jun 4.

Department of Dermatology, Ulm University, James-Franck Ring N27, 89081 Ulm, Germany.

The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and most of the assembly and maturation processes of the ribosome occur co-transcriptionally. Therefore, disturbances in rRNA transcription and processing translate to ribosomal malfunction. Read More

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http://dx.doi.org/10.3390/cells8060534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627804PMC
June 2019
5 Reads

Cytogenetic and molecular diagnosis of Fanconi anemia revealed two hidden phenotypes: Disorder of sex development and cerebro-oculo-facio-skeletal syndrome.

Mol Genet Genomic Med 2019 07 23;7(7):e00694. Epub 2019 May 23.

Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University Tunis El Manar, Tunis, Tunisia.

Background: Several studies have shown a high rate of consanguinity and endogamy in North African populations. As a result, the frequency of autosomal recessive diseases is relatively high in the region with the co-occurrence of two or more diseases.

Methods: We report here on a consanguineous Libyan family whose child was initially diagnosed as presenting Fanconi anemia (FA) with uncommon skeletal deformities. Read More

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http://dx.doi.org/10.1002/mgg3.694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625148PMC
July 2019
7 Reads

Transcription preinitiation complex structure and dynamics provide insight into genetic diseases.

Nat Struct Mol Biol 2019 06 20;26(6):397-406. Epub 2019 May 20.

Department of Chemistry, Georgia State University, Atlanta, GA, USA.

Transcription preinitiation complexes (PICs) are vital assemblies whose function underlies the expression of protein-encoding genes. Cryo-EM advances have begun to uncover their structural organization. Nevertheless, functional analyses are hindered by incompletely modeled regions. Read More

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http://dx.doi.org/10.1038/s41594-019-0220-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642811PMC
June 2019
8 Reads

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction.

Protein Cell 2020 01 30;11(1):1-22. Epub 2019 Apr 30.

Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, Beijing, 100191, China.

Cockayne syndrome (CS) is a rare autosomal recessive inherited disorder characterized by a variety of clinical features, including increased sensitivity to sunlight, progressive neurological abnormalities, and the appearance of premature aging. However, the pathogenesis of CS remains unclear due to the limitations of current disease models. Here, we generate integration-free induced pluripotent stem cells (iPSCs) from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic gene-corrected CS-iPSCs (GC-iPSCs) using the CRISPR/Cas9 system. Read More

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http://link.springer.com/10.1007/s13238-019-0623-2
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http://dx.doi.org/10.1007/s13238-019-0623-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949206PMC
January 2020
24 Reads
2.851 Impact Factor

Fine-tuning of the replisome: Mcm10 regulates fork progression and regression.

Cell Cycle 2019 05 5;18(10):1047-1055. Epub 2019 May 5.

b Department of Chemistry and Biochemistry , Baylor University , Waco , TX , USA.

Several decades of research have identified Mcm10 hanging around the replisome making several critical contacts with a number of proteins but with no real disclosed function. Recently, the O'Donnell laboratory has been better able to map the interactions of Mcm10 with a larger Cdc45/GINS/MCM (CMG) unwinding complex placing it at the front of the replication fork. They have shown biochemically that Mcm10 has the impressive ability to strip off single-strand binding protein (RPA) and reanneal complementary DNA strands. Read More

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http://dx.doi.org/10.1080/15384101.2019.1609833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592251PMC
May 2019
4 Reads

[Cockayne Syndrome].

Brain Nerve 2019 Apr;71(4):390-393

Department of Dermatology, Osaka Medical College.

Cockayne syndrome (CS) is an autosomal recessive disorder characterized by severe photosensitive genodermatosis that is associated with premature aging caused by defects in the UV-induced DNA damage repair system, particularly the transcription-coupled nucleotide excision repair. The clinical features of CS include photosensitivity, a characteristic senile face, significant developmental abnormalities, such as short stature, underweight, and microcephaly, progressive cachexia, severe visual impairment, and sensorineural deafness. CS is clinically classified into type I (classical type), type II (congenital or severe type) and type III (late-onset or adult-onset type). Read More

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http://dx.doi.org/10.11477/mf.1416201282DOI Listing
April 2019
8 Reads

Heterogeneity and overlaps in nucleotide excision repair disorders.

Clin Genet 2020 Jan 22;97(1):12-24. Epub 2019 Apr 22.

Istituto di Genetica Molecolare (IGM), Consiglio Nazionale delle Ricerche, Pavia, Italy.

Nucleotide excision repair (NER) is an essential DNA repair pathway devoted to the removal of bulky lesions such as photoproducts induced by the ultraviolet (UV) component of solar radiation. Deficiencies in NER typically result in a group of heterogeneous distinct disorders ranging from the mild UV sensitive syndrome to the cancer-prone xeroderma pigmentosum and the neurodevelopmental/progeroid conditions trichothiodystrophy, Cockayne syndrome and cerebro-oculo-facio-skeletal-syndrome. A complicated genetic scenario underlines these disorders with the same gene linked to different clinical entities as well as different genes associated with the same disease. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1111/cge.13545
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http://dx.doi.org/10.1111/cge.13545DOI Listing
January 2020
14 Reads

Functional interplay between TFIIH and KAT2A regulates higher-order chromatin structure and class II gene expression.

Nat Commun 2019 03 20;10(1):1288. Epub 2019 Mar 20.

Institut de Génétique et de Biologie Moléculaire et Cellulaire Illkirch Cedex, C.U. Strasbourg, France.

The TFIIH subunit XPB is involved in combined Xeroderma Pigmentosum and Cockayne syndrome (XP-B/CS). Our analyses reveal that XPB interacts functionally with KAT2A, a histone acetyltransferase (HAT) that belongs to the hSAGA and hATAC complexes. XPB interacts with KAT2A-containing complexes on chromatin and an XP-B/CS mutation specifically elicits KAT2A-mediated large-scale chromatin decondensation. Read More

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http://www.nature.com/articles/s41467-019-09270-2
Publisher Site
http://dx.doi.org/10.1038/s41467-019-09270-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426930PMC
March 2019
41 Reads

Homozygosity mapping and whole exome sequencing reveal a novel ERCC8 mutation in a Chinese consanguineous family with unique cerebellar ataxia.

Clin Chim Acta 2019 Jul 12;494:64-70. Epub 2019 Mar 12.

Department of Medical Genetics, College of Basic Medicine, Army Medical University (Third Military Medical University), 30#, Gaotanyan St., Shapingba District, Chongqing 400038, PR China. Electronic address:

Background: A consanguineous Chinese family was affected by an apparently novel autosomal recessive disorder characterized by cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability.

Methods: The family was evaluated by homozygosity mapping, haplotype analysis, whole exome sequencing, and candidate gene mutation screening to identify the disease-associated gene and mutation. Bioinformatics methods were used to predict the functional significance of the mutated gene product. Read More

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http://dx.doi.org/10.1016/j.cca.2019.03.1609DOI Listing
July 2019
28 Reads
2.824 Impact Factor

Molecular basis of chromatin remodeling by Rhp26, a yeast CSB ortholog.

Proc Natl Acad Sci U S A 2019 03 13;116(13):6120-6129. Epub 2019 Mar 13.

Division of Pharmaceutical Sciences, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;

CSB/ERCC6 belongs to an orphan subfamily of SWI2/SNF2-related chromatin remodelers and plays crucial roles in gene expression, DNA damage repair, and the maintenance of genome integrity. The molecular basis of chromatin remodeling by Cockayne syndrome B protein (CSB) is not well understood. Here we investigate the molecular mechanism of chromatin remodeling by Rhp26, a CSB ortholog. Read More

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http://dx.doi.org/10.1073/pnas.1818163116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442633PMC
March 2019
18 Reads

Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype.

Front Genet 2019 14;10:111. Epub 2019 Feb 14.

Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder due to a defect in the nucleotide excision repair (NER) DNA repair pathway, characterized by severe sunburn development of freckles, premature skin aging, and susceptibility to develop cancers at an average age of eight. XP is an example of accelerated photo-aging. It is a genetically and clinically heterogeneous disease. Read More

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http://dx.doi.org/10.3389/fgene.2019.00111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383105PMC
February 2019
27 Reads

Cockayne syndrome in adults: complete retinal dysfunction exploration of two case reports.

Doc Ophthalmol 2019 06 28;138(3):241-246. Epub 2019 Feb 28.

Institut Clínic d'Oftalmologia (ICOF), Hospital Clínic, Sabino de Arana St. (Casa Maternidad, 2nd floor), 08028, Barcelona, Spain.

Purpose: Cockayne syndrome is a rare autosomal recessive disease, also known as a progeria disorder, causing dwarfism, senile appearance and multiple systemic affections. Ophthalmic abnormalities are frequent, for example, in the forms of pigmentary retinopathy with low visual acuity. We present two genetic-confirmed cases with a detailed electrophysiological exploration of their retinal findings. Read More

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http://dx.doi.org/10.1007/s10633-019-09681-yDOI Listing
June 2019
16 Reads

TFIIH: A multi-subunit complex at the cross-roads of transcription and DNA repair.

Adv Protein Chem Struct Biol 2019 10;115:21-67. Epub 2019 Feb 10.

Institut de Génétique et de Biologie Moléculaire et Cellulaire Illkirch Cedex, C.U. Strasbourg, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France; Université de Strasbourg, Illkirch, France. Electronic address:

Transcription factor IIH (TFIIH) is a multiprotein complex involved in both eukaryotic transcription and DNA repair, revealing a tight connection between these two processes. Composed of 10 subunits, it can be resolved into a 7-subunits core complex with the XPB translocase and the XPD helicase, and the 3-subunits kinase complex CAK, which also exists as a free complex with a distinct function. Initially identified as basal transcription factor, TFIIH also participates in transcription regulation and plays a key role in nucleotide excision repair (NER) for opening DNA at damaged sites, lesion verification and recruitment of additional repair factors. Read More

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http://dx.doi.org/10.1016/bs.apcsb.2019.01.003DOI Listing
December 2019
6 Reads
3.036 Impact Factor