Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence

Weeda, Geert; Donker, Ingrid; Wit, Jan de; Morreau, Hans; Janssens, Roel C.; Vissers, C. J.; Nigg, Alex L.; Steeg, Harry van; Bootsma, D.; Hoeijmakers, Jan H.J.

doi:10.1016/s0960-9822(06)00190-4

Cited by 350 publications

(388 citation statements)

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“…Mouse Models-The generation and characterization of Ercc1 ϩ/Ϫ mice has been described previously (5). To achieve Purkinje cellspecific Ercc1 gene inactivation, a transgenic line with Cre recombinase under the control of the L7/pcp2 promoter was used (13 (14) were kindly provided by Dr. D. W. Melton (University of Edinburgh, Edinburgh, Scotland, UK) and backcrossed for 10 generations to obtain a pure FVB background.…”

Section: Methodsmentioning

confidence: 99%

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Spatio-temporal Analysis of Molecular Determinants of Neuronal Degeneration in the Aging Mouse Cerebellum

Graaf

Vermeij

Waard

et al. 2013

Molecular & Cellular Proteomics

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The accumulation of cellular damage, including DNA damage, is hypothesized to contribute to aging-related neurodegenerative changes. DNA excision repair crosscomplementing group 1 (Ercc1) knock-out mice represent an accepted model of neuronal aging, showing gradual neurodegenerative changes, including loss of synaptic contacts and cell body shrinkage. Here, we used the Purkinje cell-specific Ercc1 DNA-repair knockout mouse model to study aging in the mouse cerebellum. We performed an in-depth quantitative proteomics analysis, using stable isotope dimethyl labeling, to decipher changes in protein expression between the early (8 weeks), intermediate (16 weeks), and late (26 weeks) stages of the phenotypically aging Ercc1 knock-out and healthy littermate control mice. The expression of over 5,200 proteins from the cerebellum was compared quantitatively, whereby 79 proteins (i.e. 1.5%) were found to be substantially regulated during aging. Nearly all of these molecular markers of the early aging onset belonged to a strongly interconnected network involved in excitatory synaptic signaling. Using immunohistological staining, we obtained temporal and spatial profiles of these markers confirming not only the proteomics data but in addition revealed how the change in protein expression correlates to synaptic changes in the cerebellum. In summary, this study provides a highly comprehensive spatial and temporal view of the dynamic changes in the cerebellum and Purkinje cell signaling in particular, indicating that synapse signaling is one of the first processes to be affected in this premature aging model, leading to neuron morphological changes, neuron degeneration, inflammation, and ultimately behavior A link between DNA damage and the process of aging has been firmly established (1, 2). The brain in particular is a vulnerable organ that is plagued by various neurodegenerative disorders that have been related to aging, i.e. Alzheimer and Parkinson disease. The study of the early onset of agerelated neurodegenerative diseases is challenging, because there are not many confident early molecular determinants that predict their development. Therefore, progeroid syndromes (showing premature aging) are often used as a model for segmental aging as they show consistent and predictive elements of the aging phenotype (e.g. cessation of growth and development, hearing loss, and severe and progressive neuron dysfunction) (1, 3). These accelerated aging syndromes have in common that they carry defects in one or multiple proteins involved in DNA damage repair mechanisms.A well established progeroid mouse model is the excision repair cross-complementing group 1 (Ercc1) 1 gene knock-out (4, 5). The Ercc1-xeroderma pigmentosum group F complex acts as a nuclease in the nucleotide excision repair pathway and has an important function in both global genome and transcription-coupled DNA damage repair. Besides its role in nucleotide excision repair, Ercc1 is also involved in interstrand cross-link repair and oxidative damage repair. The accum...

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Section: Methodsmentioning

confidence: 99%

“…A well established progeroid mouse model is the excision repair cross-complementing group 1 (Ercc1) 1 gene knock-out (4,5). The Ercc1-xeroderma pigmentosum group F complex acts as a nuclease in the nucleotide excision repair pathway and has an important function in both global genome and transcription-coupled DNA damage repair.…”

mentioning

confidence: 99%

Spatio-temporal Analysis of Molecular Determinants of Neuronal Degeneration in the Aging Mouse Cerebellum

Graaf

Vermeij

Waard

et al. 2013

Molecular & Cellular Proteomics

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“…In addition, ERCC1 may be important for maintenance of telomere integrity by removing the 3′ overhang of uncapped telomeres and preventing telomere fusions (Zhu et al, 2003). Ercc1-/-mice are only mildly developmentally retarded, but their growth decreases dramatically by the second week of age and they have an average life span of about three weeks (McWhir et al, 1993;Weeda et al, 1997). These mutant mice exhibit early aging associated phenotypes in the skin, liver, and bone marrow, as well as ataxia, renal insufficiency, and sarcopenia.…”

Section: Suppression Of Igf-1 Signaling By Dna Damagementioning

confidence: 99%

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

Hinkal

Donehower

2008

Mechanisms of Ageing and Development

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Long-lived animals have evolved a robust set of defenses to maintain genomic integrity over their entire lifespan. The DNA damage response and DNA repair pathways are critical pillars of organismal defenses, minimizing somatic mutations in both post-mitotic and mitotic cells. These genomic maintenance systems not only prevent the premature emergence of cancers, but may also maintain normal tissue function and organismal longevity. Genetic defects in a number of DNA repair and DNA damage response genes often leads to a dramatic increase in cancer incidence; in other cases, premature aging or progeroid syndromes may be induced. In this review, we discuss two recent reports of two nucleotide excision repair deficient models that exhibit dramatic premature aging and shortened longevity. The DNA repair defects were also associated with a significant inhibition of the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis, an endocrine signaling pathway shown to influence aging and longevity in both vertebrates and invertebrates. Potential mechanisms of how DNA damage might affect IGF-1 signaling and aging are discussed, with a particular emphasis on the role of such signaling alterations in the adult tissue stem cell compartments.

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“…Fibroblasts from ERCC1 knockout mice also show a decreased rate of cell growth and disruptions in cell cycle [37] suggesting that the decrease in ERCC1 may contribute to the lengthy growth arrest in the sensitive cells.…”

Section: Changes In Ercc1 and Rad51b Are Associated With Cell Cycle Amentioning

confidence: 99%

ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair

Stordal

Davey

2008

Cancer Chemother Pharmacol

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Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence

Cited by 350 publications

References 40 publications

Spatio-temporal Analysis of Molecular Determinants of Neuronal Degeneration in the Aging Mouse Cerebellum

Spatio-temporal Analysis of Molecular Determinants of Neuronal Degeneration in the Aging Mouse Cerebellum

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair

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