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