title: Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome.
abstract: UV-sensitive syndrome (UV(S)S) and Cockayne syndrome (CS) are human disorders caused by CSA or CSB gene mutations; both conditions cause defective transcription-coupled repair and photosensitivity. Patients with CS also display neurological and developmental abnormalities and dramatic premature aging, and their cells are hypersensitive to oxidative stress. We report CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-γ catalytic subunit (POLG1), due to HTRA3 serine protease accumulation in CS, but not in UV(s)S or control fibroblasts. Inhibition of serine proteases restored physiological POLG1 levels in either CS fibroblasts and in CSB-silenced cells. Moreover, patient-derived CS cells displayed greater nitroso-redox imbalance than UV(S)S cells. Scavengers of reactive oxygen species and peroxynitrite normalized HTRA3 and POLG1 levels in CS cells, and notably, increased mitochondrial oxidative phosphorylation, which was altered in CS cells. These data reveal critical deregulation of proteases potentially linked to progeroid phenotypes in CS, and our results suggest rescue strategies as a therapeutic option.
authors.affiliation: Institut Pasteur, Department of Genomes and Genetics, Unité de Génétique Moléculaire des Levures, 75724 Paris, France; CNRS UMR 3525, Team Stability of Nuclear and Mitochondrial DNA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chatre
authors.affiliation: Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institute of Emerging Diseases and Innovative Therapies (iMETI), Division of Prions and Related Diseases (SEPIA), Team Cellular Engineering and Human Syndromes, F-92265 Fontenay-aux-Roses, France;
authors.forename: Denis S F
authors.initials: DS
authors.lastname: Biard
authors.affiliation: UMR 8200 CNRS Laboratory of Genetic Stability and Oncogenesis, Institut de cancérologie Gustave Roussy, and University Paris-Sud, 114 rue Edouard Vaillant, 94805 Villejuif, France; and Department of Genetics, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Sarasin
authors.affiliation: Institut Pasteur, Department of Genomes and Genetics, Unité de Génétique Moléculaire des Levures, 75724 Paris, France; CNRS UMR 3525, Team Stability of Nuclear and Mitochondrial DNA, mricch@pasteur.fr.
authors.forename: Miria
authors.initials: M
authors.lastname: Ricchetti
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D003057:Cockayne Syndrome / Q000188:drug therapy* / Q000473:pathology; D004265:DNA Helicases / Q000378:metabolism*; D000074002:DNA Polymerase gamma; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000473:pathology; D030421:Peroxynitrous Acid / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011371:Progeria / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004272:DNA, Mitochondrial; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species; D015842:Serine Proteinase Inhibitors; D030421:Peroxynitrous Acid; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes
keywords: Cockayne syndrome; DNA polymerase gamma; mtSSB; premature ageing; serine protease