title: Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging.
abstract: Defects in the DNA repair mechanism nucleotide excision repair (NER) may lead to tumors in xeroderma pigmentosum (XP) or to premature aging with loss of subcutaneous fat in Cockayne syndrome (CS). Mutations of mitochondrial (mt)DNA play a role in aging, but a link between the NER-associated CS proteins and base excision repair (BER)-associated proteins in mitochondrial aging remains enigmatic. We show functional increase of CSA and CSB inside mt and complex formation with mtDNA, mt human 8-oxoguanine glycosylase (mtOGG)-1, and mt single-stranded DNA binding protein (mtSSBP)-1 upon oxidative stress. MtDNA mutations are highly increased in cells from CS patients and in subcutaneous fat of aged Csb(m/m) and Csa(-/-) mice. Thus, the NER-proteins CSA and CSB localize to mt and directly interact with BER-associated human mitochondrial 8-oxoguanine glycosylase-1 to protect from aging- and stress-induced mtDNA mutations and apoptosis-mediated loss of subcutaneous fat, a hallmark of aging found in animal models, human progeroid syndromes like CS and in normal human aging.
authors.affiliation: Department of Dermatology, Eberhard Karls University, D-72076 Tuebingen, Germany.
authors.forename: York
authors.initials: Y
authors.lastname: Kamenisch
authors.forename: Maria
authors.initials: M
authors.lastname: Fousteri
authors.forename: Jennifer
authors.initials: J
authors.lastname: Knoch
authors.forename: Anna-Katharina
authors.initials: AK
authors.lastname: von Thaler
authors.forename: Birgit
authors.initials: B
authors.lastname: Fehrenbacher
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.forename: Thomas
authors.initials: T
authors.lastname: Becker
authors.forename: Martijn E T
authors.initials: ME
authors.lastname: Dollé
authors.forename: Raoul
authors.initials: R
authors.lastname: Kuiper
authors.forename: Marc
authors.initials: M
authors.lastname: Majora
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
authors.forename: Doron
authors.initials: D
authors.lastname: Rapaport
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
authors.forename: Leon H
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Mark
authors.initials: M
authors.lastname: Berneburg
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D003057:Cockayne Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D045647:DNA Glycosylases / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C490652:Ckn1 protein, mouse; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; C095472:ERCC8 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C479058:oxoguanine glycosylase 1, human; D004265:DNA Helicases; C078673:ERCC6 protein, human; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes