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General Comment |
One of the factors postulated to drive the aging process is the accumulation of DNA
damage. de Boer J et al 2002 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.
NCBI Summary:
The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
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General function |
Cell death/survival, Apoptosis, DNA repair, Enzyme, Hydrolase, Nucleic acid binding, DNA binding, Transcription factor
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Mutations |
2 mutations
Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: TTD females appeared to lose fertility over time de Boer J et al 2002 , and to lose it
early, because they never produced more than one litter and never after 6 months of age. TTD females (n = 8, age ~16
months) displayed ovarian dysfunction ranging from complete anovulation to sporadic, seemingly normal, ovulation.
Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: Premature aging in mice deficient in DNA repair and transcription. de Boer J et al. (2002) 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.//////////////////
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