Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1−/− mice

Prasher, Joanna M.; Lalai, Astrid S.; Heijmans-Antonissen, Claudia; Ploemacher, Rob E.; Hoeijmakers, Jan H.J.; Touw, Ivo P.; Niedernhofer, Laura J.

doi:10.1038/sj.emboj.7600542

Cited by 124 publications

(107 citation statements)

References 59 publications

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“…Recently, it was reported that Ercc1 −/− mice also display hematopoietic aging as both basal hematopoiesis and reserve capacity under stress were severely reduced in these mice, consistent with that found in normal aged mice [102]. However, the premature liver polyploidy, as was reported in Ercc1 −/− mice, differs from the normal aging-related process, as the observed dramatic increased p21 levels in Ercc1 −/− livers were absent in livers of normal aging mice with the same amount of polyploidy [103].…”

Section: Many Of the Features Of The Ercc1supporting

confidence: 63%

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

Wijnhoven

Hoogervorst

Waard

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) areexcept for the skin -not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features.

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Section: Many Of the Features Of The Ercc1supporting

confidence: 63%

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

Wijnhoven

Hoogervorst

Waard

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…As more fully described in recent reviews, DNA damage has been linked to stem cell attrition in a number of experimental contexts (Blasco, 2007;Rando, 2006;Sharpless and DePinho, 2007). Perhaps most relevant to the two NER papers discussed here, Prasher et al (Prasher et al, 2005) have shown that 3 week old Ercc1-/-mice exhibit multilineage cytopenia and fatty replacement of bone marrow, similar to old wild type mice. Moreover, hematopoietic progenitor numbers and proliferative reserves were dramatically decreased in the Ercc1-/-mice compared to their wild type counterparts.…”

Section: How Does the Dna Damage Response Affect Tissue Homeostasis?mentioning

confidence: 84%

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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“…Furthermore, in the absence of XPF-ERCC1 there is a defect in recruitment of FANCD2 to chromatin [116]. Most compellingly, the phenotype of Ercc1-deficient mice has significant overlap with FA exhibiting growth retardation, blood cytopenias, developmental defects and sterility [113,117,118]. It is important to note that the sterility observed in Ercc1-deficient mice is a pattern of primordial germ cell failure the unifying feature of all FA mouse models [118].…”

Section: A Specific Molecular Defect In Fanconi Anaemiamentioning

confidence: 99%

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

Crossan

Patel

2011

The Journal of Pathology

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Fanconi anaemia (FA) is a rare, autosomal recessive, genetically complex, DNA repair deficiency syndrome in man. Patients with FA exhibit a heterogeneous spectrum of clinical features. The most significant and consistent phenotypic characteristics are stem cell loss, causing progressive bone marrow failure and sterility, diverse developmental abnormalities and a profound predisposition to neoplasia. To date, 15 genes have been indentified, biallelic disruption of any one of which results in this clinically defined syndrome. It is now apparent that all 15 gene products act in a common process to maintain genome stability. At the molecular level, a fundamental defect in DNA repair underlies this complex phenotype. Cells derived from FA patients spontaneously accumulate broken chromosomes and exhibit a marked sensitivity to DNA-damaging chemotherapeutic agents. Despite complementation analysis defining many components of the FA DNA repair pathway, no direct link to DNA metabolism was established until recently. First, it is now evident that the FA pathway is required to make incisions at the site of damaged DNA. Second, a specific component of the FA pathway has been identified that regulates nucleases previously implicated in DNA interstrand crosslink repair. Taken together, these data provide genetic and biochemical evidence that the FA pathway is a bona fide DNA repair pathway that directly mediates DNA repair transactions, thereby elucidating the specific molecular defect in human Fanconi anaemia.

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Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1−/− mice

Cited by 124 publications

References 59 publications

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

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

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

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