Premature Aging in Mice Deficient in DNA Repair and Transcription

@article{deBoer2002PrematureAI,
  title={Premature Aging in Mice Deficient in DNA Repair and Transcription},
  author={Johan G de Boer and Jaan-Olle Andressoo and Jan de Wit and Jan G. M. Huijmans and Rudolf B. Beems and Harry van Steeg and Geert Weeda and Gijsbertus T J van der Horst and Wibeke J. Van Leeuwen and Axel P. N. Themmen and Morteza Meradji and Jan H. J. Hoeijmakers},
  journal={Science},
  year={2002},
  volume={296},
  pages={1276 - 1279}
}
One of the factors postulated to drive the aging process is the accumulation of DNA damage. [...] Key Result 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…Expand
Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice.
TLDR
It is concluded that while increased genomic instability could play a causal role in the mildly accelerated aging phenotype in the Xpa-null mice or in the severe progeroid symptoms of the Ercc1-mutant mice, shortened lifespan in mice with defects in transcription-related repair do not depend upon increased mutation accumulation. Expand
NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging
TLDR
The NRMT1 knockout mouse is positioned as a useful new system for studying the effects of genomic instability and defective DNA damage repair on organismal and tissue-specific aging. Expand
Premature aging with impaired oxidative stress defense in mice lacking TR4.
TLDR
A novel role of TR4 in mediating the interplay between oxidative stress defense and aging is identified, which supports the hypothesis that the premature aging in TR4(-/-) mice might stem from oxidative DNA damage caused by increased oxidative stress or compromised genome integrity. Expand
Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice
TLDR
The results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis and a compensatory adjustment to limit the increased genotoxic stress in these mutants. Expand
Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform.
TLDR
In vivo evidence is shown that the absence of the Brca1 full-length isoform causes senescence in mutant embryos and cultured cells as well as aging and tumorigenesis in adult mice, providing the first in vivo evidence that links cellsenescence to aging due to impaired function of Brca2 at the expense of tumorigenisation. Expand
DNA double-strand breaks: A potential causative factor for mammalian aging?
TLDR
Compared mouse models of premature aging that are defective for repairing either double-strand breaks (DSBs) or UV light-induced lesions are compared to believe the basic mechanisms responsible for their aging phenotypes are fundamentally different demonstrating the complex and pleiotropic nature of this process. Expand
Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms
TLDR
Intriguingly, highly conserved longevity assurance mechanisms respond to transcription-blocking DNA lesions in mammals as well as in worms and counteract the detrimental consequences of persistent DNA damage. Expand
The Contribution of DNA Interstrand Crosslinks to Aging
TLDR
Collectively, these studies identified genes, environmental influences and therapeutics that impact lifespan and healthspan that strongly support the hypothesis that DNA damage can promote degenerative changes associated with aging. Expand
Premature aging and cancer in nucleotide excision repair-disorders.
TLDR
Similar principles likely apply to other DNA repair pathways including interstrand crosslink repair and double strand break repair and genome maintenance systems in general, supporting the notion that DNA damage constitutes an important intermediate in the process of aging. Expand
Deletion of Ku80 causes early aging independent of chronic inflammation and Rag-1-induced DSBs
Animal models of premature aging are often defective for DNA repair. Ku80-mutant mice are disabled for nonhomologous end joining; a pathway that repairs both spontaneous DNA double-strand breaksExpand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 54 REFERENCES
Defective Transcription-Coupled Repair in Cockayne Syndrome B Mice Is Associated with Skin Cancer Predisposition
TLDR
It is demonstrated that transcription-coupled repair of UV-induced cyclobutane pyrimidine dimers contributes to the prevention of carcinogenesis in mice and suggested that the lack of cancer predisposition in CS patients is attributable to a global genome repair process that in humans is more effective than in rodents. Expand
Deletion of Ku86 causes early onset of senescence in mice.
TLDR
DNA double-strand breaks formed during the assembly of antigen receptors or after exposure to ionizing radiation are repaired by proteins important for nonhomologous end joining that include Ku86, Ku70, DNA-PK(CS), Xrcc4, and DNA ligase IV, which indicate that Ku86-dependent chromosomal metabolism is important for determining the onset of age-specific changes characteristic of senescence in mice. Expand
Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence
TLDR
The results strongly suggest that the accumulation in ERCC1-mutant mice of endogenously generated DNA interstrand cross-links, which are normally repaired by ER CC1-dependent recombination repair, underlies both the early onset of cell cycle arrest and polyploidy in the liver and kidney. Expand
The Werner Syndrome: A Model for the Study of Human Aging
TLDR
Recent evidence, summarized in this review, suggests specific bio‐chemical roles for this multifaceted protein WRN functions as a DNA helicase, and the interaction of WRN protein with RPA (replication protein A and p53 will undoubtedly direct efforts to further dissect the genetic pathway(s) in which WRNprotein functions in DNA metabolism and will help to unravel its contribution to the human aging process. Expand
p53 mutant mice that display early ageing-associated phenotypes
TLDR
It is suggested that p53 has a role in regulating organismal ageing by generating mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. Expand
A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy.
TLDR
Using a novel gene-targeting strategy, this work has mimicked the causative XPD point mutation of a TTD patient in the mouse, strongly supporting the concept of TTD as a human disease due to inborn defects in basal transcription and DNA repair. Expand
Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation
TLDR
Findings provide the first evidence that the lack of activation of Mdm2 plays a key role in the cascade of events leading to apoptosis, indicating that the persistence of DNA damage in the transcribed strand of active genes leads to apoptOS. Expand
Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition.
TLDR
A mouse model for trichothiodystrophy is used that mimics an XPD point mutation of a TTD patient in the mouse germline and supports the notion that a NER deficiency enhances cancer susceptibility. Expand
Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice
TLDR
A critical role for telomere length in the overall fitness, reserve, and well being of the aging organism is demonstrated. Expand
Telomerase and mammalian ageing: a critical appraisal
TLDR
It appears that in vitro replicative senescence, which has been observed in cultured somatic cells, is due to a loss of telomere length in those cells, caused by inactivity of telomerase, leading to the proposition that telomersase activity is an important determinant in organismal ageing. Expand
...
1
2
3
4
5
...