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^XPCSXpa 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.

ACKNOWLEDGMENTS

We are very grateful to Mart Saarma, Urmas Arumäe, and Maria Lindahl for critical reading, to Saara Ollila for essential editing of the manuscript, and to Ruud Koppenol and Tom de Vries for photography.

This research was supported by the Netherlands Organization for Scientific Research (NWO), through the foundation of the Research Institute for Diseases of the Elderly, The Netherlands Genomic Initiative, as well as grants from the National Institutes of Health (1PO1 AG17242-02), the National Institute of Environmental Health Sciences (1UO1 ES011044), the European Commission (QRTL-1999-02002), and the Dutch Cancer Society (EUR 99-2004). J.R.M. was a fellow of the Damon Runyon Cancer Research Fund (DRG 1677). J.O.A. is the fellow of the Academy of Finland, postdoctoral research grant no. 108973 and 214526. J.H.H. is CSO of Pharming.