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Molecular and Cellular Biology, March 2009, p. 1276-1290, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01229-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

An Xpb Mouse Model for Combined Xeroderma Pigmentosum and Cockayne Syndrome Reveals Progeroid Features upon Further Attenuation of DNA Repair{triangledown}

Jaan-Olle Andressoo,1,{dagger},§ Geert Weeda,1,§ Jan de Wit,1,§ James R. Mitchell,1,{ddagger},§ Rudolf B. Beems,2,§ Harry van Steeg,2,§ Gijsbertus T. J. van der Horst,1,§ and Jan H. Hoeijmakers1,§*

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,1 National Institute of Public Health and Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands2

Received 5 August 2008/ Returned for modification 5 September 2008/ Accepted 2 December 2008

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 XPBXPCS 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 XpbXPCS 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 XpbXPCS 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.

* Corresponding author. Mailing address: 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. Phone: 31 10 408-9468. Fax: 31 (0)10 704-4743. E-mail: j.hoeijmakers{at}erasmusmc.nl

{triangledown} Published ahead of print on 29 December 2008.

{dagger} Present address: Institute of Biotechnology, Viikinkaari 9, 00014 Helsinki, Finland.

§ J.O.A., G.W., J.H.H., and G.T.J.V.D.H. conceived and designed the experiments. J.O.A., G.W., J.D.W., J.R.M., and R.B.B. performed the experiments. J.O.A., J.D.W., J.H.H., H.V.S., and J.R.M. analyzed the data. J.H.H. and G.T.J.V.D.H. contributed reagents/materials/analysis tools. J.O.A., J.R.M., and J.H.H. wrote the paper.

{ddagger} Present address: Harvard School of Public Health, 655 Huntington Avenue 2-121, Boston, MA.

Molecular and Cellular Biology, March 2009, p. 1276-1290, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01229-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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