A Mouse Model for the Basal Transcription/DNA Repair Syndrome Trichothiodystrophy

Boer, Jan de; Wit, Jan de; Steeg, Harry van; Berg, Rob J. W.; Morreau, Hans; Visser, Pim; Lehmann, Alan R.; Durán, Marinus; Hoeijmakers, J.H.J.; Weeda, Geert

doi:10.1016/s1097-2765(00)80098-2

Cited by 188 publications

(140 citation statements)

References 32 publications

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“…Importantly, the DDB2 Ϫ/Ϫ (XPE) mice did not exhibit any abnormality in DMBA-induced carcinogenesis, whereas mouse models that are defective in NER genes such as XPA (23,28), XPD (29), or CSB (24) show abnormal skin cancer predisposition after either UV-irradiation or exposure to DMBA, presumably because these mice are defective in proteins directly involved in NER and cannot normally repair bulky DNA adducts in general. By contrast, TP53 Ϫ/Ϫ mice do not increase initiation or promotion of DMBA-induced skin tumors (30), strongly supporting the proposal that DDB2 is involved in controlling p53 levels and͞or its activity after UV-irradiation.…”

Section: Discussionmentioning

confidence: 99%

DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen

Itoh

Cado²,

Kamide³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the human DDB2 gene give rise to xeroderma pigmentosum group E, a disease characterized by increased skin tumorigenesis in response to UV-irradiation. Cell strains derived from xeroderma pigmentosum group E individuals also have enhanced resistance to UV-irradiation due to decreased p53-mediated apoptosis. To further address the precise function(s) of DDB2 and the consequence of non-naturally occurring DDB2 mutations, we generated mice with a disruption of the gene. The mice exhibited significantly enhanced skin carcinogenesis in response to UV-irradiation, and cells from the DDB2 ؊/؊ mice were abnormally resistant to killing by the radiation and had diminished UVinduced, p53-mediated apoptosis. Notably, the cancer-prone phenotype and the resistance to cellular killing were not observed after exposure to the chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), to which mice carrying defective nucleotide excision repair genes respond with enhanced tumors and cell killing. Although cells from heterozygous DDB2 ؉/؊ mice appeared normal, these mice had enhanced skin carcinogenesis after UVirradiation, so that XP-E heterozygotes might be at risk for carcinogenesis. In sum, these results demonstrate that DDB2 is well conserved between humans and mice and functions as a tumor suppressor, at least in part, by controlling p53-mediated apoptosis after UV-irradiation.T he disease xeroderma pigmentosum (XP) group E is one of eight subgroups of the cancer-prone syndrome, XP, and it has been associated with mutations in the DDB2 gene (1-4) that codes for the smaller subunit of the heterodimeric damagespecific DNA binding protein, DDB (5, 6). DDB strongly binds to DNA damages caused by UV light, including (6-4) photoproducts and trans,syn-cyclobutane pyrimidine dimers, yet it does not have a strong affinity for cis,syn-cyclobutane pyrimidine dimers, the most abundant UV photoproduct (5, 7-11).The binding to DNA damages might suggest a direct role for DDB in nucleotide excision repair (NER) and DNA repair assays with rodent Chinese hamster ovary cell lines that lack DDB2 expression combined with ectopic overexpression of DDB2 cDNA led to the conclusion that DDB2 is a repair factor involved in global genomic repair, a subpathway of NER. However, the removal from DNA of many bulky lesions, including (6-4) photoproducts, occurs in the absence of DDB (8, 12, 13), and DDB2 is induced by UV-irradiation at a time by which NER has been completed. Moreover, the DDB2 promoter resembles that of a cell cycleregulated gene (1, 14), and DDB2 is part of the COP9 signalosome complex (15, 16). Instead, DDB2 has been proposed to be a transcription transactivator through its stimulation of E2F1 (17), and we recently observed that DDB2 controls p53-mediated apoptosis after UV-irradiation of human diploid fibroblasts and that XP group E (XP-E) primary skin fibroblasts are abnormally resistant to killing by . In sum, the functions of DDB are apparently varied and remain undefined.The absence of DDB2 from Chinese hamster ovary cel...

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Section: Discussionmentioning

confidence: 99%

DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen

Itoh

Cado²,

Kamide³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Compe et al [44] studied the so-called TTD mouse, which carries the same R722W mutation in Xpd as in a human TTD patient [45]. They first showed that total brain weights of the TTD mice at postnatal day 20 were significantly lower than WT controls, and also observed some evidence for reduced myelination.…”

Section: A New Concept Of the Transcription Syndrome Hypothesis: Lossmentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

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“…However, the mouse model in which the causative XPD R722W mutation of a TTD patient is mimicked is viable [92]. Xpd R722W mice further indicated as Xpd TTD mice, just like the TTD patients, do not suffer from enhanced spontaneous tumorigenesis.…”

Section: Mouse Models With a Defect In Ner And Transcriptionmentioning

confidence: 99%

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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A Mouse Model for the Basal Transcription/DNA Repair Syndrome Trichothiodystrophy

Cited by 188 publications

References 32 publications

DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen

DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

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