TY - JOUR
T1 - Premature aging in mice deficient in DNA repair and transcription
AU - De Boer, Jan
AU - Andressoo, Jaan Olle
AU - De Wit, Jan
AU - Huijmans, Jan
AU - Beems, Rudolph B.
AU - Van Steeg, Harry
AU - Weeda, Geert
AU - Van der Horst, Gijsbertus T.J.
AU - Van Leeuwen, Wibeke
AU - Themmen, Axel P.N.
AU - Meradji, Morteza
AU - Hoeijmakers, Jan H.J.
PY - 2002/5/17
Y1 - 2002/5/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037123638&partnerID=8YFLogxK
U2 - 10.1126/science.1070174
DO - 10.1126/science.1070174
M3 - Article
C2 - 11950998
AN - SCOPUS:0037123638
SN - 0036-8075
VL - 296
SP - 1276
EP - 1279
JO - Science
JF - Science
IS - 5571
ER -