Cell Reports (Jun 2024)
Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system
- Cherif Badja,
- Sophie Momen,
- Gene Ching Chiek Koh,
- Soraya Boushaki,
- Theodoros I. Roumeliotis,
- Zuza Kozik,
- Ian Jones,
- Vicky Bousgouni,
- João M.L. Dias,
- Marios G. Krokidis,
- Jamie Young,
- Hongwei Chen,
- Ming Yang,
- France Docquier,
- Yasin Memari,
- Lorea Valcarcel-Zimenez,
- Komal Gupta,
- Li Ren Kong,
- Heather Fawcett,
- Florian Robert,
- Salome Zhao,
- Andrea Degasperi,
- Yogesh Kumar,
- Helen Davies,
- Rebecca Harris,
- Christian Frezza,
- Chryssostomos Chatgilialoglu,
- Robert Sarkany,
- Alan Lehmann,
- Chris Bakal,
- Jyoti Choudhary,
- Hiva Fassihi,
- Serena Nik-Zainal
Affiliations
- Cherif Badja
- 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; Corresponding author
- Sophie Momen
- 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
- Gene Ching Chiek Koh
- 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
- Soraya Boushaki
- 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
- Theodoros I. Roumeliotis
- Functional Proteomics Group, Institute of Cancer Research, Chester Betty Labs, 237 Fulham Road, London SW3 6JB, UK
- Zuza Kozik
- Functional Proteomics Group, Institute of Cancer Research, Chester Betty Labs, 237 Fulham Road, London SW3 6JB, UK
- Ian Jones
- Dynamical Cell Systems Laboratory, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
- Vicky Bousgouni
- Dynamical Cell Systems Laboratory, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
- João M.L. Dias
- 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
- Marios G. Krokidis
- 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
- Jamie Young
- 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
- Hongwei Chen
- 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
- Ming Yang
- 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
- France Docquier
- Department of Medical Genetics, Box 238, Level 6, Addenbrooke’s Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK
- Yasin Memari
- 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
- Lorea Valcarcel-Zimenez
- 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
- Komal Gupta
- Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK
- Li Ren Kong
- 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 Institute of Singapore, Singapore 117599, Singapore
- Heather Fawcett
- Genome Damage and Stability Centre, University of Sussex, Brighton, UK
- Florian Robert
- 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
- Salome Zhao
- 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
- Andrea Degasperi
- Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK
- Yogesh Kumar
- Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK
- Helen Davies
- 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
- Rebecca Harris
- Department of Medical Genetics, Box 238, Level 6, Addenbrooke’s Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK
- Christian Frezza
- 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
- Chryssostomos Chatgilialoglu
- 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
- Robert Sarkany
- National Xeroderma Pigmentosum Service, St John’s Institute of Dermatology, Guy’s and St Thomas’ Foundation Trust, London SE1 7EH, UK
- Alan Lehmann
- Genome Damage and Stability Centre, University of Sussex, Brighton, UK
- Chris Bakal
- Dynamical Cell Systems Laboratory, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
- Jyoti Choudhary
- Functional Proteomics Group, Institute of Cancer Research, Chester Betty Labs, 237 Fulham Road, London SW3 6JB, UK
- Hiva Fassihi
- National Xeroderma Pigmentosum Service, St John’s Institute of Dermatology, Guy’s and St Thomas’ Foundation Trust, London SE1 7EH, UK
- Serena Nik-Zainal
- 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; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 6
p. 114243
Abstract
Summary: 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.
