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Published Online April 11, 2002
Science DOI: 10.1126/science.1070174

Research Articles

Submitted on January 24, 2002
Accepted on March 15, 2002

Premature Aging in Mice Deficient in DNA Repair and Transcription

Jan de Boer 1, Jaan Olle Olle Andressoo 2, Jan de Wit 2, Jan Huijmans 3, Rudolph B. Beems 4, Harry van Steeg 4, Geert Weeda 2, Gijsbertus T. J. van der Horst 2, Wibeke van Leeuwen 5, Axel P. N. Themmen 6, Morteza Meradji 7, Jan H. J. Hoeijmakers 2*

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

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

One theory on aging involves accumulation of DNA damage. Here we provide strong support for this hypothesis by studying 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). The 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 repair defect, showed a greatly accelerated aging phenotype, that correlated with an increased cellular sensitivity to oxidative DNA damage. We hypothesize that aging in the TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and apoptosis.


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