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Science 296 (5571): 1276-1279

Copyright © 2002 by the American Association for the Advancement of Science

Premature Aging in Mice Deficient in DNA Repair and Transcription

Jan de Boer,1* Jaan Olle Andressoo,1 Jan de Wit,1 Jan Huijmans,2 Rudolph B. Beems,5 Harry van Steeg,5 Geert Weeda,1 Gijsbertus T. J. van der Horst,1 Wibeke van Leeuwen,3 Axel P. N. Themmen,4 Morteza Meradji,6 Jan H. J. Hoeijmakers1dagger

One of the factors postulated to drive the aging process is the accumulation of DNA damage. Here, we provide strong support for this hypothesis by describing studies of mice with a mutation in XPD, a gene encoding a DNA helicase that functions in both repair and transcription and that is mutated in the human disorder trichothiodystrophy (TTD). TTD mice were found to exhibit many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early greying, cachexia, infertility, and reduced life-span. TTD mice carrying an additional mutation in XPA, which enhances the DNA repair defect, showed a greatly accelerated aging phenotype, which correlated with an increased cellular sensitivity to oxidative DNA damage. We hypothesize that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis.

1 Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics,
2 MGC-Department of Clinical Genetics, CBG,
3 Department of Experimental Radiology,
4 Department of Endocrinology and Reproduction, Post Office Box 1738, Erasmus University, 3000 DR Rotterdam, Netherlands.
5 National Institute of Public Health and the Environment, Post Office Box 1, 3720 BA Bilthoven, Netherlands.
6 Department of Radiology, Sophia Kinderziekenhuis, Rotterdam, Netherlands.
*   Present address: Isotis N.V., Prof. Bronkhorstlaan 10 D, 3723 MB Bilthoven, Netherlands.

dagger    To whom correspondence should be addressed. E-mail: hoeijmakers{at}gen.fgg.eur.nl



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