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Sikandar G. Khan Koji Yamanegi Zhi‐Ming Zheng Jennifer Boyle Kyoko Imoto Kyu‐Seon Oh Carl C. Baker Engin Gozukara Ahmet Metin Kenneth H. Kraemer 《Human mutation》2010,31(2):167-175
Mutations in two branch‐point sequences (BPS) in intron 3 of the XPC DNA repair gene affect pre‐mRNA splicing in association with xeroderma pigmentosum (XP) with many skin cancers (XP101TMA) or no skin cancer (XP72TMA), respectively. To investigate the mechanism of these abnormalities we now report that transfection of minigenes with these mutations revealed abnormal XPC pre‐mRNA splicing that mimicked pre‐mRNA splicing in the patients' cells. DNA oligonucleotide‐directed RNase H digestion demonstrated that mutations in these BPS disrupt U2 snRNP–BPS interaction. XP101TMA cells had no detectable XPC protein but XP72TMA had 29% of normal levels. A small amount of XPC protein was detected at sites of localized ultraviolet (UV)‐damaged DNA in XP72TMA cells which then recruited other nucleotide excision repair (NER) proteins. In contrast, XP101TMA cells had no detectable recruitment of XPC or other NER proteins. Post‐UV survival and photoproduct assays revealed greater reduction in DNA repair in XP101TMA cells than in XP72TMA. Thus mutations in XPC BPS resulted in disruption of U2 snRNP‐BPS interaction leading to abnormal pre‐mRNA splicing and reduced XPC protein. At the cellular level these changes were associated with features of reduced DNA repair including diminished NER protein recruitment, reduced post‐UV survival and impaired photoproduct removal. Hum Mutat 30:1–9, 2009. Published 2009 Wiley‐Liss, Inc. 相似文献
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B C Hamel A Raams A R Schuitema-Dijkstra P Simons I van der Burgt N G Jaspers W J Kleijer 《Journal of medical genetics》1996,33(7):607-610
We report on a male patient born to healthy, first cousin, Moroccan parents. During the pregnancy growth retardation was observed. Birth weight, length, and OFC were all well below the 3rd centile. Facial anomalies, microphthalmia, cleft palate, small penis, and flexion contractures of large joints were noted. Cerebral MRI showed dysmyelination. The clinical course was characterised by feeding difficulties, growth failure, lack of development, photosensitivity, and death at 7 months. The main differential diagnoses were COFS syndrome and early onset Cockayne syndrome (CS). UV exposure of cultured fibroblasts showed inhibition of nucleic acids synthesis. Further DNA repair studies showed extreme cellular sensitivity to UV and xeroderma pigmentosum (XP)-like defective nucleotide excision repair (NER), which in combination with the clinical symptoms indicated the very rare XP-CS complex. Complementation analysis showed that the XPG gene is affected in this patient. In cases suspected of having COFS syndrome and early onset CS, extensive DNA repair studies are needed to reach the definitive diagnosis, thereby allowing reliable genetic counselling and prenatal diagnosis. 相似文献
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Boyle J Ueda T Oh KS Imoto K Tamura D Jagdeo J Khan SG Nadem C Digiovanna JJ Kraemer KH 《Human mutation》2008,29(10):1194-1208
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Correlation of Phenotype/Genotype in a Cohort of 23 Xeroderma Pigmentosum‐Variant Patients Reveals 12 New Disease‐Causing POLH Mutations
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Wei Yang Caroline Pouvelle Jacques Armier Emmanuelle Despras Ludovic Martin Christine Mateus Caroline Robert Patricia Kannouche Nadem Soufir Alain Sarasin 《Human mutation》2014,35(1):117-128
Xeroderma pigmentosum variant (XP‐V) is a rare genetic disease, characterized by some sunlight sensitivity and predisposition to cutaneous malignancies. We described clinical and genetic features of the largest collection ever published of 23 XP‐V patients (ages between 21 and 86) from 20 unrelated families. Primary fibroblasts from patients showed normal nucleotide excision repair but UV‐hypersensitivity in the presence of caffeine, a signature of the XP‐V syndrome. 87% of patients developed skin tumors with a median age of 21 for the first occurrence. The median numbers of basal‐cell carcinoma was 13 per patient, six for squamous‐cell carcinoma, and five for melanoma. XP‐V is due to defects in the translesion‐synthesis DNA polymerase Polη coded by the POLH gene. DNA sequencing of POLH revealed 29 mutations, where 12 have not been previously identified, leading to truncated polymerases in 69% of patients. Four missense mutations are correlated with the protein stability by structural modeling of the Polη polymerase domain. There is a clear relationship between the types of missense mutations and clinical severity. For truncating mutations, which lead to an absence of or to inactive proteins, the life‐cumulated UV exposure is probably the best predictor of cancer incidence, reinforcing the necessity to protect XP‐Vs from sun exposure. 相似文献
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Ad5HCMVsp1lacZ is a recombinant nonreplicating adenovirus containing the lacZ gene under the control of the human cytomegalovirus immediate early promoter. Previous reports show that lacZ expression for UV-irradiated Ad5HCMVsp1lacZ is greater in nucleotide excision repair (NER) proficient compared to NER deficient human fibroblasts from patients with xeroderma pigmentosum (XP) and Cockaye's syndrome (CS) and that pre-UV-treatment of normal fibroblasts results in an enhanced expression of the lacZ gene from UV-irradiated Ad5HCMVsp1lacZ. We have used a quantitative PCR technique to examine whether UV photoproducts are actually removed from the lacZ gene following infection of human fibroblasts with UV-irradiated Ad5HCMVsp1lacZ. Primers flanking a 2.6-kb region of the lacZ reporter gene were added to equal amounts of DNA extracted from Ad5HCMVsp1lacZ infected cells and amplified by PCR using radiolabelled nucleotides as substrates. Results show a significant removal of UV photoproducts in normal human fibroblasts, but a reduced removal in NER deficient XP and CS cells and an enhanced removal in pre-UV-treated normal fibroblasts. 相似文献
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《Mutation Research/DNA Repair》1994,314(3):233-248
We report here on two siblings who show no clinical manifestations except for slight cutaneous photosensitivity and cutaneous pigmentation but have biochemical characteristics o Cockayne syndrome (CS). Fibroblasts derived DNA synthesis (UDS)_in these cells was at a normal level, recovery of RNA synthesis (RRS) after UV irradiation was severely depressed. Microinjection of bacteriophage T4 endonuclease V into the cells corrected RRS after UV irradiation to a level near normal. These results indicate that DNA repair of cyclobutane-type pyrimidine dimers is impaired in the cells and the biochemical characteristics are similar to these of CS cells. However, cell fusion complementation tests with CS group A and B cells resulted in correction of RRS after UV irradiation. Cell fusion with XP group A, B, D, F and G cells also corrected RRS after UV irradiation, and microinjection of cell extracts prepared from Kps3 cells corrected UDS in XP group C and E cells, indicating that the patients do not belong to any complementation group of XP or CS. These results suggest that the patients have a new UV-sensitive syndrome with a biochemical phenotype of CS. 相似文献
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Shuttle vector plasmids pYZ289 were irradiated with UV and transfectedto mouse cells to permit repair of damage, mutation and replicationin the cells. The frequency and types of mutations were comparedwith those of UV-irradiated shuttle vector plasmids pZ189 whichwere propagated in normal human and xeroderma pigmentosum (XP)patient cells defective in DNA repair. Both shuttle vector plasmidscontain a bacterial suppressor tRNA gene supF as a common mutationtarget. pYZ289 propagated in the mouse cells showed survivaland mutation frequency similar to pZ189 propagated in the normalhuman cells. All single base substitution mutations were inducedin dipyrimidine sequences and G: C to A: T transition was mostfrequently observed (47%) in the mouse cells; however, the frequencywas significantly lower than that in the XP cells. The frequencyof the base substitution mutations at A: T base pairs was significantlyhigher in the mouse cells (29%) than in the normal human (12%)and the XP cells (6%). These results show that similar typesof mutations are induced by UV in mouse and normal human cells,and that the A: T base pair is relatively more mutable in mousethan in normal human and XP cells. 相似文献
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Human mediator MED17 subunit plays essential roles in gene regulation by associating with the transcription and DNA repair machineries
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Yuko Kikuchi Hiroyasu Umemura Saori Nishitani Satoshi Iida Rikiya Fukasawa Hiroto Hayashi Yutaka Hirose Aki Tanaka Kaoru Sugasawa Yoshiaki Ohkuma 《Genes to cells : devoted to molecular & cellular mechanisms》2015,20(3):191-202
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Akahoshi K Moriwaki S Kimiya S Takahashi I Fukushima Y 《American journal of medical genetics》2001,101(2):153-157
We report a Japanese woman with de novo 6p monosomy and 10q trisomy [46,XX,der(6)t(6;10)(p25.1;q25.2)] whose clinical manifestations resemble those of xeroderma pigmentosum (XP) and Cockayne syndrome (CS), known as premature aging syndromes. She had a history of easy sunburning and presented a number of freckles and hypopigmented spots on her face as those of XP. Magnetic resonance imaging and computed tomography scanning demonstrated intracranial abnormalities like those seen in CS. DNA repair studies using the patient's fibroblasts demonstrated hypersensitive responses to ultraviolet (UV). XP, CS, and UV-sensitive syndromes with photosensitivity disturbances have been known as DNA repair abnormalities. However, an association of 6p monosomy with these diseases has not been reported so far. Molecular analysis of the patient we described may contribute to the identification of novel DNA-repair-related gene(s) and/or to the senile mechanism. 相似文献
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Xeroderma pigmentosum (XP) is a rare, recessively inherited genodermatosis prone to ultraviolet (UV)-induced skin neoplasms from keratinocyte origin, i.e. basal and squamous cell carcinoma. Cells from classic XP patients fail to properly eliminate UV-induced DNA lesions by the nucleotide excision repair (NER) mechanism. A variant form of XP, called XP-V suffers from faulty translesion synthesis. We review here recent data on XP gene products whose alterations affect NER and result in one of the 7 complementation groups of XP. Encouraging results of retrovirus-based genetic correction of XP keratinocytes are summarized and support realistic prospects of gene therapy for the XP-C complementation group. 相似文献