Human DDB2 splicing variants are dominant negative inhibitors of UV-damaged DNA repair

Inoki, Taeko; Yamagami, Satoru; Inoki, Yutaka; Tsuru, Tadahiko; Hamamoto, Toshiro; Kagawa, Yasuo; Mori, Toshio; Endo, Hitoshi

doi:10.1016/j.bbrc.2004.01.003

Cited by 17 publications

(17 citation statements)

References 29 publications

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“…Those tissues also expressed the splice-variant lacking exon 4 only. Interestingly, that splice-variant was not observed in human tissues (Inoki et al, 2004). Thus, there are differences in the splicing patterns that generate the minor DDB2 splice-variants in humans and mice.…”

Section: Targeted Disruption Of the Mouse Ddb2 Genementioning

confidence: 91%

“…The human DDB2 gene exhibits a broad expression pattern based on RT-PCR assays of total RNA from various human tissues, including heart, lung, liver, brain and others (Inoki et al, 2004). To investigate the expression pattern of mouse DDB2, we analysed total RNA from muscle, lung, liver, pancreas, spleen and bone marrow.…”

Section: Targeted Disruption Of the Mouse Ddb2 Genementioning

confidence: 99%

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Tumor-prone phenotype of the DDB2-deficient mice

et al. 2004

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DDB2 is an essential subunit of the damaged-DNA recognition factor DDB, which is involved in global genomic repair in human cells. Moreover, DDB2 is mutated in the repair-deficiency disease xeroderma pigmentosum (Group E). Expression of DDB2 in human cells is induced by P53, BRCA1 and by ionizing radiation. The DDB2 protein associates with transcriptional activator and coactivator proteins. In addition, DDB2 in conjunction with DDB1 associates with cullin 4A and the Cop9/signalosome. We generated a mouse strain deficient for DDB2 (DDB2À/À). Consistent with the human disease (XP-E), the DDB2À/À mice were susceptible to UV-induced skin carcinogenesis. We observed a significant difference in the initial rate of cyclobutane pyrimidine dimer (CPD)-removal from the skin following UV irradiation. Also, the DDB2-deficient mice exhibited a significantly reduced life span compared to their wild-type littermates. Moreover, unlike other XP-deficient mice, the DDB2-deficient mice developed spontaneous malignant tumors at a high rate between the ages of 20 and 25 months. The observations suggest that, in addition to DNA repair, the other interactions of DDB2 are significant in its tumor suppression function.

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Section: Targeted Disruption Of the Mouse Ddb2 Genementioning

confidence: 91%

Section: Targeted Disruption Of the Mouse Ddb2 Genementioning

confidence: 99%

Tumor-prone phenotype of the DDB2-deficient mice

et al. 2004

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“…To the best of our knowledge, the alternative splicing of XPA has not been reported so far. Frequently, the alternatively spliced mRNA molecules are less efficiently translated than the major mRNA forms [38], and sometimes they produce protein molecules showing a dominant-negative effect [39] or are aberrantly localised [40]. It remains to be determined whether the alternatively spliced form of XPA mRNA has physiological significance or if it is merely a product of the imperfect splicing.…”

Section: Discussionmentioning

confidence: 99%

A functional analysis of G23A polymorphism and the alternative splicing in the expression of the XPA gene

Butkiewicz

Krześniak

Vaitiekunaite

et al. 2010

Cellular and Molecular Biology Letters

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Abstract:The XPA gene has a commonly occurring polymorphism (G23A) associated with cancer risk. This study assessed the functional significance of this polymorphism, which is localised near the translation start codon. Lymphoblastoid cell lines with alternative homozygous genotypes showed no significant differences in their XPA levels. The luciferase reporter assay detected no functional difference between the two sequences. Unexpectedly, we found that the alternatively spliced form of XPA mRNA lacked a part of exon 1. Only the reading frame downstream of codon Met59 was preserved. The alternative mRNA is expressed in various human tissues. The analysis of the 5'cDNA ends showed similar transcription start sites for the two forms. The in vitro expression of the alternative XPA labelled with the red fluorescent protein (mRFP) showed a lack of preferential nuclear accumulation of the XPA isoform. The biological role of the alternative XPA mRNA form remains to be elucidated.

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“…DDB2 is ubiquitously expressed in human tissues, with the highest level being found in corneal endothelium and the lowest level in the brain. Isoform D1 is highly expressed in brain and heart tissues, whereas isoforms D2, D3, and D4 are weakly expressed in these tissues (Inoki et al, 2004). Interestingly, repair of DNA damage induced by UV light appears to be less active in brain and heart tissues which are naturally protected against UV irradiation and express high levels of isoform D1.…”

Section: Ddb2 Recognizes Dna Damage During Global Genome Nermentioning

confidence: 99%

“…Strikingly, structural analysis of DDB bound to DNA duplex containing 6-4PP has revealed that the DDB2 subunit is responsible for the interaction, and this subunit induces the movement of the two affected bases into a binding pocket, therefore indicating that DDB has evolved to specifically recognize dinucleotide lesions, like UV photolesions [ Figure 1; Scrima et al, 2008]. Furthermore, accumulating evidence has confirmed the existence of multiple forms of DDB2 mRNA splicing variants, including isoforms D1 and D2, which do not interact with DDB1, but inhibit UV-damaged DNA repair (Inoki et al, 2004). DDB2 is ubiquitously expressed in human tissues, with the highest level being found in corneal endothelium and the lowest level in the brain.…”

Section: Ddb2 Recognizes Dna Damage During Global Genome Nermentioning

confidence: 99%

The Role of DDB2 in Regulating Cell Survival and Apoptosis Following DNA Damage - A Mini-Review

Chao¹

2011

DNA Repair

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Human DDB2 splicing variants are dominant negative inhibitors of UV-damaged DNA repair

Cited by 17 publications

References 29 publications

Tumor-prone phenotype of the DDB2-deficient mice

Tumor-prone phenotype of the DDB2-deficient mice

A functional analysis of G23A polymorphism and the alternative splicing in the expression of the XPA gene

The Role of DDB2 in Regulating Cell Survival and Apoptosis Following DNA Damage - A Mini-Review

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