We are very grateful to Steven Bergink, Koos Jaspers, and Bjorn Schumacher for thoughtful discussions and critical reading of the manuscript and to Ruud Koppenol and Tom de Vries for photography. Author contributions. JOA, JJ, JHJH, GTJvdH, and JRM conceived and designed the experiments. JOA, JJ, JdW, FC, DH, MvdV, WT, JH, WJvL, and JRM performed the experiments. JOA, JJ, JdW, FC, DH, MvdV, JH, HBT, WJvL, JME, JHJH, and JRM analyzed the data. JdB and GTJvdH contributed reagents/materials/analysis tools. JOA, JHJH, and JRM wrote the paper. Funding. This research was supported by the Netherlands Organization for Scientific Research (NWO) through the foundation of the Research Institute for Diseases of the Elderly, as well as grants from the National Institutes of Health (1PO1 AG17242–02), National Institute of Environmental Health Sciences (1UO1 ES011044), European Commission (QRTL-1999–02002), and the Dutch Cancer Society (EUR 99–2004). JRM was a fellow of the Damon Runyon Cancer Research Fund (DRG 1677). Competing interests. The authors have declared that no competing interests exist. ¤a Current address: Institute of Biotechnology, University of Helsinki, Helsinki, Finland ¤b Current address: Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, United States of America ¤c Current address: Institute for Biomedical Technology, University of Twente, Bilthoven, Netherlands Abbreviations bp base pair CS Cockayne syndrome E[number] embryonic day [number] kb kilobase NER nucleotide excision repair SEM standard error of the mean TFIIH basal transcription/DNA repair factor IIH TTD trichothiodystrophy UV-RRS recovery of RNA synthesis after ultraviolet irradiation UV-UDS unscheduled DNA synthesis after ultraviolet irradiation wt wild-type XP xeroderma pigmentosum XPCS xeroderma pigmentosum combined with Cockayne syndrome XPTTD combination xeroderma pigmentosum and trichothiodystrophy