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Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system.
Badja, Cherif; Momen, Sophie; Koh, Gene Ching Chiek; Boushaki, Soraya; Roumeliotis, Theodoros I; Kozik, Zuza; Jones, Ian; Bousgouni, Vicky; Dias, João M L; Krokidis, Marios G; Young, Jamie; Chen, Hongwei; Yang, Ming; Docquier, France; Memari, Yasin; Valcarcel-Zimenez, Lorea; Gupta, Komal; Kong, Li Ren; Fawcett, Heather; Robert, Florian; Zhao, Salome; Degasperi, Andrea; Kumar, Yogesh; Davies, Helen; Harris, Rebecca; Frezza, Christian; Chatgilialoglu, Chryssostomos; Sarkany, Robert; Lehmann, Alan; Bakal, Chris; Choudhary, Jyoti; Fassihi, Hiva; Nik-Zainal, Serena.
Afiliación
  • Badja C; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK. Electronic a
  • Momen S; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Koh GCC; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Boushaki S; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Roumeliotis TI; Functional Proteomics Group, Institute of Cancer Research, Chester Betty Labs, 237 Fulham Road, London SW3 6JB, UK.
  • Kozik Z; Functional Proteomics Group, Institute of Cancer Research, Chester Betty Labs, 237 Fulham Road, London SW3 6JB, UK.
  • Jones I; Dynamical Cell Systems Laboratory, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
  • Bousgouni V; Dynamical Cell Systems Laboratory, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
  • Dias JML; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Krokidis MG; Institute of Nanoscience and Nanotechnology, N.C.S.R. "Demokritos", Agia Paraskevi Attikis, 15310 Athens, Greece; Bioinformatics and Human Electrophysiology Laboratory, Department of Informatics, Ionian University, 49100 Corfu, Greece.
  • Young J; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Chen H; Wellcome Sanger Institute, Hinxton CB10 1RQ, UK; Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.
  • Yang M; Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; CECAD Research Center, Faculty of Medicine, University Hospital Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
  • Docquier F; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK.
  • Memari Y; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Valcarcel-Zimenez L; Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; CECAD Research Center, Faculty of Medicine, University Hospital Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
  • Gupta K; Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
  • Kong LR; Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; NUS Centre for Cancer Research, N2CR, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; Cancer Science Institut
  • Fawcett H; Genome Damage and Stability Centre, University of Sussex, Brighton, UK.
  • Robert F; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Zhao S; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Degasperi A; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Kumar Y; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Davies H; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.
  • Harris R; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK.
  • Frezza C; Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; CECAD Research Center, Faculty of Medicine, University Hospital Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
  • Chatgilialoglu C; Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy; Center for Advanced Technologies, Adam Mickiewicz University, 61-614 Poznan, Poland.
  • Sarkany R; National Xeroderma Pigmentosum Service, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, UK.
  • Lehmann A; Genome Damage and Stability Centre, University of Sussex, Brighton, UK.
  • Bakal C; Dynamical Cell Systems Laboratory, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
  • Choudhary J; Functional Proteomics Group, Institute of Cancer Research, Chester Betty Labs, 237 Fulham Road, London SW3 6JB, UK.
  • Fassihi H; National Xeroderma Pigmentosum Service, St John's Institute of Dermatology, Guy's and St Thomas' Foundation Trust, London SE1 7EH, UK.
  • Nik-Zainal S; Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK. Electronic a
Cell Rep ; 43(6): 114243, 2024 Jun 25.
Article en En | MEDLINE | ID: mdl-38805398
ABSTRACT
Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We show substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.
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Texto completo: 1 Colección: 01-internacional Asunto principal: Xerodermia Pigmentosa / Células Madre Pluripotentes Inducidas Límite: Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Asunto principal: Xerodermia Pigmentosa / Células Madre Pluripotentes Inducidas Límite: Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article