Publication Date:
2002-04-16
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Boer, Jan -- Andressoo, Jaan Olle -- de Wit, Jan -- Huijmans, Jan -- Beems, Rudolph B -- van Steeg, Harry -- Weeda, Geert -- van der Horst, Gijsbertus T J -- van Leeuwen, Wibeke -- Themmen, Axel P N -- Meradji, Morteza -- Hoeijmakers, Jan H J -- AG 17242-02/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2002 May 17;296(5571):1276-9. Epub 2002 Apr 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University, 3000 DR Rotterdam, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11950998" target="_blank"〉PubMed〈/a〉
Keywords:
*Aging
;
Aging, Premature/*etiology
;
Animals
;
Apoptosis
;
Bone Density
;
Cachexia/etiology
;
Crosses, Genetic
;
*DNA Damage
;
DNA Helicases/genetics/*physiology
;
*DNA Repair
;
DNA-Binding Proteins/genetics/physiology
;
Female
;
Fertility
;
Gene Targeting
;
Growth Disorders/etiology/genetics
;
Hair Diseases/genetics
;
Kyphosis/etiology/genetics/pathology
;
Male
;
Mice
;
Mutation
;
Oxidative Stress
;
Phenotype
;
Point Mutation
;
Proteins/genetics/*physiology
;
RNA-Binding Proteins/genetics/physiology
;
*Transcription Factors
;
Transcription, Genetic
;
Xeroderma Pigmentosum Group A Protein
;
Xeroderma Pigmentosum Group D Protein
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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