title: Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.
abstract: As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Barnhoorn
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lieneke M
authors.initials: LM
authors.lastname: Uittenboogaard
authors.affiliation: Department of Neuroscience, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Jaarsma
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wilbert P
authors.initials: WP
authors.lastname: Vermeij
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Tresini
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Weymaere
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Hervé
authors.initials: H
authors.lastname: Menoni
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Renata M C
authors.initials: RM
authors.lastname: Brandt
authors.affiliation: Department of Intensive Care, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.affiliation: Uniklinik Balgrist, Zürich, Switzerland.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Botter
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors.forename: Altaf H
authors.initials: AH
authors.lastname: Sarker
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Nicolaas G J
authors.initials: NG
authors.lastname: Jaspers
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Cooper
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology; D002100:Cachexia / Q000209:etiology / Q000235:genetics; D002490:Central Nervous System / Q000502:physiology / Q000503:physiopathology; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003677:Deficiency Diseases / Q000209:etiology* / Q000235:genetics; D004195:Disease Models, Animal; D004720:Endonucleases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D008099:Liver / Q000473:pathology; D008136:Longevity / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010024:Osteoporosis / Q000209:etiology / Q000235:genetics; D011247:Pregnancy; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5