An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria

Jaan Olle Andressoo, James R. Mitchell, Jan de Wit, Deborah Hoogstraten, Marcel Volker, Wendy Toussaint, Ewoud Speksnijder, Rudolph B. Beems, Harry van Steeg, Judith Jans, Chris I. de Zeeuw, Nicolaas G.J. Jaspers, Anja Raams, Alan R. Lehmann, Wim Vermeulen, Jan H.J. Hoeijmakers, Gijsbertus T.J. van der Horst

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)121-132
Number of pages12
JournalCancer Cell
Volume10
Issue number2
DOIs
Publication statusPublished - Aug 2006
Externally publishedYes

Keywords

  • DNA

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