title: An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair.
abstract: Patients carrying mutations in the XPB helicase subunit of the basal transcription and nucleotide excision repair (NER) factor TFIIH display the combined cancer and developmental-progeroid disorder xeroderma pigmentosum/Cockayne syndrome (XPCS). Due to the dual transcription repair role of XPB and the absence of animal models, the underlying molecular mechanisms of XPB(XPCS) are largely uncharacterized. Here we show that severe alterations in Xpb cause embryonic lethality and that knock-in mice closely mimicking an XPCS patient-derived XPB mutation recapitulate the UV sensitivity typical for XP but fail to show overt CS features unless the DNA repair capacity is further challenged by crossings to the NER-deficient Xpa background. Interestingly, the Xpb(XPCS) Xpa double mutants display a remarkable interanimal variance, which points to stochastic DNA damage accumulation as an important determinant of clinical diversity in NER syndromes. Furthermore, mice carrying the Xpb(XPCS) mutation together with a point mutation in the second TFIIH helicase Xpd are healthy at birth but display neonatal lethality, indicating that transcription efficiency is sufficient to permit embryonal development even when both TFIIH helicases are crippled. The double-mutant cells exhibit sensitivity to oxidative stress, suggesting a role for endogenous DNA damage in the onset of XPB-associated CS.
authors.affiliation: MGC-Cancer Genomics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus Medical Center, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: Jaan-Olle
authors.initials: JO
authors.lastname: Andressoo
authors.forename: Geert
authors.initials: G
authors.lastname: Weeda
authors.forename: Jan
authors.initials: J
authors.lastname: de Wit
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
authors.forename: Rudolf B
authors.initials: RB
authors.lastname: Beems
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: Jan H
authors.initials: JH
authors.lastname: Hoeijmakers
mesh_terms: D000818:Animals; D003057:Cockayne Syndrome / Q000150:complications*; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair; D004195:Disease Models, Animal; D051379:Mice; D009154:Mutation; D018384:Oxidative Stress; D051758:Transcription Factor TFIIH / Q000235:genetics; D014983:Xeroderma Pigmentosum / Q000150:complications*
chemical_list: D051758:Transcription Factor TFIIH; D004265:DNA Helicases