title: An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria.
abstract: Inborn defects in nucleotide excision DNA repair (NER) can paradoxically result in elevated cancer incidence (xeroderma pigmentosum [XP]) or segmental progeria without cancer predisposition (Cockayne syndrome [CS] and trichothiodystrophy [TTD]). We report generation of a knockin mouse model for the combined disorder XPCS with a G602D-encoding mutation in the Xpd helicase gene. XPCS mice are the most skin cancer-prone NER model to date, and we postulate an unusual NER dysfunction that is likely responsible for this susceptibility. XPCS mice also displayed symptoms of segmental progeria, including cachexia and progressive loss of germinal epithelium. Like CS fibroblasts, XPCS and TTD fibroblasts from human and mouse showed evidence of defective repair of oxidative DNA lesions that may underlie these segmental progeroid symptoms.
authors.affiliation: Medical Genetics Center, Department of Cell Biology and Genetics, Center of Biomedical Genetics, Cancer Genomics Center, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
authors.forename: Jaan-Olle
authors.initials: JO
authors.lastname: Andressoo
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
authors.forename: Jan
authors.initials: J
authors.lastname: de Wit
authors.forename: Deborah
authors.initials: D
authors.lastname: Hoogstraten
authors.forename: Marcel
authors.initials: M
authors.lastname: Volker
authors.forename: Wendy
authors.initials: W
authors.lastname: Toussaint
authors.forename: Ewoud
authors.initials: E
authors.lastname: Speksnijder
authors.forename: Rudolph B
authors.initials: RB
authors.lastname: Beems
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Judith
authors.initials: J
authors.lastname: Jans
authors.forename: Chris I
authors.initials: CI
authors.lastname: de Zeeuw
authors.forename: Nicolaas G J
authors.initials: NG
authors.lastname: Jaspers
authors.forename: Anja
authors.initials: A
authors.lastname: Raams
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
authors.forename: Wim
authors.initials: W
authors.lastname: Vermeulen
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D003057:Cockayne Syndrome / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D004260:DNA Repair; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010212:Papilloma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011371:Progeria / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D014983:Xeroderma Pigmentosum / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; C497293:Ercc2 protein, mouse