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A Newly Identified Patient with Clinical Xeroderma Pigmentosum Phenotype Has a Non-Sense Mutation in the DDB2 Gene and Incomplet

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A Newly Identified Patient with Clinical Xeroderma Pigmentosum Phenotype Has a Non-Sense Mutation in the DDB2 Gene and Incomplet View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector A Newly Identified Patient with Clinical Xeroderma Pigmentosum Phenotype has a Non-Sense Mutation in the DDB2 Gene and Incomplete Repair in (6-4) Photoproducts Toshiki Itoh, Toshio Mori,† Hiroaki Ohkubo,* and Masaru Yamaizumi Department of Cell Genetics, *Gene Regulation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto, Japan; and †Radioisotope Center, Nara Medical University, Nara, Japan We report here a patient (Ops1) with clinical photosen- pattern repair in cis-syn cyclobutane sitivity, including pigmented or depigmented macules pyrimidine dimers by repair kinetics using the enzyme- and patches, and multiple skin neoplasias (malignant linked immunosorbent assay. Moreover, Ops1 cells melanomas, basal cell carcinomas, and squamous cell were defective in a damage-specific DNA binding carcinomas in situ) in sun-exposed areas. These clinical protein and carried a non-sense mutation in the DDB2 features are reminiscent of xeroderma pigmentosum. gene. These results suggest that (i) the DDB2 gene is As cells from Ops1 showed normal levels in DNA somewhat related to skin carcinogenesis, photoaging repair synthesis in vivo (unscheduled DNA synthesis and skin, and the removal of (6-4) photoproducts; (ii) although it is believed that cyclobutane pyrimidine recovery of RNA synthesis after ultraviolet irradiation), dimers are the principal mutagenic lesion and (6-4) we performed a postreplication repair assay and recov- photoproducts are less likely to contribute to ultravi- ery of replicative DNA synthesis after ultraviolet irradi- olet-induced mutations in mammals, Ops1 is one of ation to investigate if Ops1 cells belonged to a the ultraviolet-induced mutagenic models induced by xeroderma pigmentosum variant pattern. Ops1 cells (6-4) photoproducts. Key words: damage-specific DNA were normal, but there was an incomplete pattern binding protein/nucleotide excision repair/postreplication repair in (6-4) photoproducts in contrast to a normal repair. J Invest Dermatol 113:251–257, 1999 eroderma pigmentosum (XP) is a rare autosomal levels of caffeine enhanced the lethal effect of UV light in XP-V recessive disease characterized by a clinical and cells (Arlett et al, 1975; Cleaver and Kraemer, 1995). As the cellular hypersensitivity to ultraviolet (UV) light defective gene in XP-V has not yet been cloned, it is necessary (Cleaver and Kraemer, 1995). Patients exhibit to detect abnormal semiconservative DNA replication after UV dermatologic abnormalities, including thickening irradiation, that is, postreplication repair (PRR), for the definite Xand hyperpigmentation of sun-exposed skin, and develop sunlight- diagnosis of XP-V (Lehmann et al, 1975, 1977; Rude and Friedberg, induced malignancies at an earlier age than usual. Cells from XP 1977; Cleaver and Kraemer, 1995). In addition, we recently patients show hypersensitivity to killing by UV irradiation and reported a simple alternative method for the diagnosis of XP-V severely reduced levels of unscheduled DNA synthesis (UDS). This (Itoh et al, 1996a). This technique provided a systematic procedure cellular phenotype correlates with a defect in nucleotide-excision- for diagnosis in photosensitive patients with NER defective XP or repair (NER) of UV-induced DNA lesions. By cell fusion analyses, PRR defective XP (Itoh et al, 1996a). XP was defined as having seven genetic complementation groups A damage-specific DNA binding (DDB) protein was first (XP-A through XP-G). A separate group XP variant (XP-V), had reported by Feldberg and Grossman (1976). It has a broad proficient NER. XP-V showed an exaggerated delay in recovery specificity, binding to DNA damaged by UV light, ionizing of replicative DNA synthesis (RDS) after UV irradiation (Lehmann radiation, NaHSO3, OsO4, and an enzymatic superoxide-generating et al, 1975, 1977; Rude and Friedberg, 1977; Cleaver and Kraemer, system (Feldberg and Grossman, 1976; Feldberg, 1980; Feldberg et al, 1982; Carew and Feldberg, 1985). In particular, a DDB 1995), and continuous postirradiation treatment with nontoxic protein bound with a high affinity to UV photoproducts: trans,syn-I cyclobutane pyrimidine dimers (CPD) (6-4) photoproducts [(6-4) PP], and Dewar isomer of the (6-4) PP, but with only a marginal Manuscript received November 12, 1998; revised April 12, 1999; affinity to cis-syn CPD. A binding with the psoralen-thymine accepted for publication April 21, 1999. monoadduct was not measurably detected (Reardon et al, 1993). Reprint requests to: Toshiki Itoh, Department of Cell Genetics, NER was originally defined in terms of the removal of cis-syn Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kuhonji 4-24-1, Kumamoto, 862-0976, Japan. CPD from DNA in both prokaryotes and eukaryotes (Friedberg E-mail: [email protected] et al, 1995). Moreover, NER defective XP (XP-A through XP- Abbreviations: (6-4) PP, (6-4) photoproducts; CPD, cyclobutane pyrimi- G) is defective in the removal of cis-syn CPD and the psoralen- dine dimers; DDB, damage-specific DNA binding; NER, nucleotide- thymine monoadduct, and is not usually sensitive to most of these excision-repair; PRR, postreplication repair; RRS, recovery of RNA agents, except for UV photoproducts (Friedberg et al, 1995). Thus, synthesis; RDS, recovery of replicative DNA synthesis; UDS, unscheduled it seemed that DDB protein was somewhat related with DNA DNA synthesis; XP, xeroderma pigmentosum. repair, but was not directly related with NER or NER defective XP. 0022-202X/99/$14.00 · Copyright © 1999 by The Society for Investigative Dermatology, Inc. 251 252 ITOH ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY In the course of surveying photosensitive patients, we had a as a defect of DDB protein in this study. The human primary cell strain chance to diagnose an interesting case. The patient, a 62 y old XP82TO (XP-E) was a gift from Dr. Seiji Kondo at Tokyo Medical and Japanese woman (Ops1), showed a clinical XP phenotype. In this Dental University (Kondo et al, 1988). The human primary cell strain, study, we extensively examined biochemical characteristics of Ops1 XP2SA (XP-V) was purchased from the Human Science Research Resources Bank (Osaka, Japan). All cells were cultured in Dulbecco’s cells including NER or PRR assays established previously (Itoh modified Eagle’s minimum essential medium (ICN, Irvine, CA) supple- et al, 1994, 1995, 1996a). Interestingly, while the cells showed mented with 10% (vol/vol) fetal bovine serum (ICN), penicillin G (100 NER activity within a normal range, the repair kinetics of (6-4) units per ml), and streptomycin (100 µg per ml) in a humidified 5% PP was selectively impaired. Moreover, Ops1 cells showed a CO2 incubator. defective DDB protein. These results suggest the possibility that Ops1 had a phenotype other than the already known XP, as Ops1 UV survival assay Colony forming ability was performed as described showed normal NER and PRR, and was involved in the repair of elsewhere (Itoh et al, 1994, 1995). Cells were trypsinized and appropriate specific types of DNA damage. numbers of cells were plated on to 60 mm plates. After incubation for 10 h, they were washed with phosphate-buffered saline, irradiated with MATERIALS AND METHODS various doses of UVC (254 nm) at a fluence rate of 0.7 J per m2 per s, and then fresh medium was applied. After 1–2 wk, the plates were washed Cells and culture conditions The human primary cell strains Mori, with phosphate-buffered saline, fixed with 80% (vol/vol) methanol, stained Turu, and Sono were established as normal in this laboratory (Itoh et al, with Giemsa, and colonies were counted. Survival curves were plotted on 1994, 1995, 1996a). The human primary cell strain Ops1 was designated semilogarithmic paper. To determine the effect of caffeine on UV survival, cells were plated, washed, and irradiated as described above. Caffeine was added at a final concentration of 1 mM just after UV irradiation and the plates were incubated for 2 wk. Figure 1. UV survival of Ops1 cells. Appropriate numbers of cells were inoculated on to 60 mm dishes. After UV irradiation at a fluence rate of 0.7 J per m2 per s, cells were incubated for 14 d, fixed with 80% methanol, Figure 2. Rate of DNA synthesis after UV irradiation in Ops1 cells. and stained with Giemsa. Caffeine was added at a final concentration of Cells were irradiated with UV light at a dose of 5 J per m2. After 0, 2, 4, 1 mM just after UV irradiation. Each point represents an average of three 6, or 8 h incubation, cells were pulse-labeled with [3H]thymidine (10 µCi or four experiments; error bar: SEM. Mori cells (u) were used as a normal per ml) for 30 min. Mori cells (u) were used as a normal control. Each control. Ops1 cells (s); Ops1 cells with 1 mM caffeine (d); XP2SA (XP- value is the mean for three or four experiments; error bar: SEM. Ops1 cells V) cells (n); XP2SA cells with 1 mM caffeine (m). (s); XP2SA cells (XP-V) (n). Table I. DNA repair levels in vivo in Ops1 cells Cell straina Grains/nucleus Range of relative rate (%)b UDS Ops1/Moric 14.4 6 0.3/13.9 6 0.3 99–108 Ops1/Turuc 12.8 6 0.3/ 9.8 6 0.3 124–138 Ops1/Sonoc 8.9 6 0.2/ 8.3 6 0.2 102–112 RRS Ops1/Morid 48.6 6 3.9/40.2 6 3.9 101–145 With caffeine Without caffeine With caffeine Without caffeine RDS 59.9 6 6.4/66.1 6 5.9 72.2 6 4.2/62.0 6 5.9 74–110 100–136 Ops1/Morid aMori, Turo, and Sono are normal control cells. bRange of relative rate are the values (grain-numbers) of Ops1 cells compared with those of normal cells.
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