Harefuah. 2006 Dec;145(12):889-94, 942.

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[Clinical, biochemical and molecular characterization of rare genetic disorders, related to nucleotide excision repair (NER) system]

[Article in Hebrew]

Falik-Zaccai T, Kfir N, Laskar M, Segel R, Khyat M, Slor H.

Institute of Human Genetics, Western Galilee Hospital, Naharia, Israel. tzipora.falik@naharia.health.gov.il

All living organisms are equipped with DNA repair systems that can cope with a wide variety of DNA lesions. Among these repair pathways, nucleotide excision repair (NER) is quite versatile, involved in the removal of a variety of bulky DNA lesions induced by ultraviolet light and chemical carcinogens and mutagens. The importance of NER for human health is illustrated mainly by the occurrence of rare life-threatening disorders such as Xeroderma Pigmentosum (XP), Cockayne Syndrome (CS) and Trichthiodystrophy (TTD). XP, CS and most TTD patients exhibit increased sensitivity to UV light and premature aging. XP is associated with a high incidence of skin tumors, CS is primarily a developmental disorder associated with failure to thrive, and psychomotor retardation. The authors report the clinical, biochemical and molecular aspects of the NER pathway in individuals suspected to have a DNA repair, NER type-related disease. These diseases are rare worldwide, but are frequent in Israel, probably due to the high rate of consanguinity among certain Arab, Druze and Jewish populations. Our laboratory is the only one in Israel, and one of very few labs world-wide that is performing DNA repair evaluation as a diagnostic test for DNA repair-deficient inherited diseases. Identification of the causative genes and proteins in suspected families will facilitate accurate diagnosis, genetic counseling, identification of couples at risk and prenatal diagnosis.

Publication Types:

English Abstract


PMID: 17220027 [PubMed - in process]

Nature. 2006 Dec 21;444(7122):1015-7.

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Comment on:

Nature. 2006 Dec 21;444(7122):1038-43.

Ageing: too fast by mistake.

Kirkwood T.

Publication Types:

Comment

News


PMID: 17183304 [PubMed - indexed for MEDLINE]

Gynecol Oncol. 2006 Dec;103(3):891-6. Epub 2006 Jun 23.

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Nucleotide excision repair genotype and the incidence of endometrial cancer: effect of other risk factors on the association.

Weiss JM, Weiss NS, Ulrich CM, Doherty JA, Chen C.

Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA. weissjoc@mail.nih.gov

OBJECTIVES: Certain nucleotide excision repair (NER) genotypes appear to be associated with an altered risk of endometrial cancer. These associations could be modified by characteristics and exposures that themselves influence risk of disease. METHODS: We conducted a population-based case-control study in western Washington State to address the role of specific NER genotypes in conjunction with relevant exposures, such as postmenopausal hormone therapy, obesity, parity, oral contraceptive use, and cigarette smoking on risk of endometrial cancer. Case women (n=371), ages 50-69 years, were diagnosed with invasive endometrial cancer between 1994 and 1999. Control women (n=420), matched to cases on age and county of residence, were selected using random-digit dialing (ages 50-65) and random selection from HCFA data files (ages 66-69). RESULTS: Risk of endometrial cancer was not associated with ERCC1, ERCC2 (XPD), ERCC4 (XPF), or ERCC5 (XPG) genotype. A reduced risk of endometrial cancer was observed with presence of the XPA g23a variant allele, but only among women with a history of oral contraceptive use (OR 0.47, 95% CI 0.32-0.69). A decreased risk associated with carriage of at least one variant allele for both XPC A499V and XPC K939Q was restricted to women with BMI<30 kg/m2 (OR 0.45, 95% CI 0.25-0.82). The size of the association between these genotypes and risk of endometrial cancer did not differ by postmenopausal hormone use, parity, or smoking. CONCLUSIONS: Our study provides limited evidence for interactions between NER genotypes and DNA damage-causing exposures in the etiology of endometrial cancer. Subsequent studies are needed to confirm the observed associations.

Publication Types:

Research Support, N.I.H., Extramural

Research Support, Non-U.S. Gov't


PMID: 16806437 [PubMed - indexed for MEDLINE]

Breast Cancer Res Treat. 2006 Jan;95(1):73-80. Epub 2005 Dec 1.

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Polymorphisms of the DNA repair genes XPD (Lys751Gln) and XRCC1 (Arg399Gln and Arg194Trp): relationship to breast cancer risk and familial predisposition to breast cancer.

Brewster AM, Jorgensen TJ, Ruczinski I, Huang HY, Hoffman S, Thuita L, Newschaffer C, Lunn RM, Bell D, Helzlsouer KJ.

Department of Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1439, USA. abrewster@mdanderson.org

Family history is a risk factor for breast cancer and could be due to shared environmental factors or polymorphisms of cancer susceptibility genes. Deficient function of DNA repair enzymes may partially explain familial risk as polymorphisms of DNA repair genes have been associated, although inconsistently, with breast cancer. This population based case-control study examined the association between polymorphisms in XPD (Lys751Gln) and XRCC1 (Arg399Gln and Arg194Trp) genes, and breast cancer. Breast cancer cases (n=321) and controls (n=321) were matched on age and menopausal status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). The analysis was conducted omitting observations with missing data, and by using imputation methods to handle missing data. No significant association was observed between the XPD 751Gln/Lys (OR 1.37, 95% CI 0.96-1.96) and Gln/Gln genotypes (OR 1.08, 95% CI 0.62-1.86) (referent Lys/Lys), XRCC1 399Arg/Gln (OR 1.48, 95% CI 0.92-2.38) and Gln/Gln genotypes (1.11, 95% CI 0.67-1.83) (referent Arg/Arg) or the XRCC1 Arg/Trp and Trp/Trp genotypes (OR 1.12, 95% CI 0.69-1.83) (referent Arg/Arg) and breast cancer. In multivariate analysis, the adjusted odds ratios for the XPD and XRCC1 399 polymorphisms increased and became statistically significant, however, were attenuated when imputation methods were used to handle missing data. There was no interaction with family history. These results indicate that these polymorphisms in XPD and XRCC1 genes are only weakly associated with breast cancer. Without imputation methods for handling missing data, a statistically significant association was observed between the genotypes and breast cancer, illustrating the potential for bias in studies that inadequately handle missing data.

Publication Types:

Comparative Study

Research Support, N.I.H., Extramural

Research Support, Non-U.S. Gov't


PMID: 16319991 [PubMed - indexed for MEDLINE

 

J Dermatolog Treat. 2006;17(4):241-3.

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Xeroderma pigmentosum and lentigo maligna in identical twins.

Faghihi G, Radan M.

Department of Dermatology, Shahid Beheshti Hospital, Isfahan University School of Medicine, Isfahan, Iran.

Xeroderma pigmen tosum (XP) is a rare autosomal recessive genodermatosis. Skin abnormalities result from an inability to repair UV-damaged DNA. Clinically, XP presents with early onset cutaneous changes (severe photosensitivity, actinic keratoses, and telangiectasias) and an increase of developing cutaneous malignancies beginning in early childhood, but lentigo maligna and melanomas are relatively rare. Here we report on homozygote twins in whom there was no positive family history. They showed subnormal physical growth. On ophthalmological examination, both had photophobia and decreased visual acuity. Since birth, several excisions had been performed for skin neoplasms. In one of them a pigmented patch developed over the frontal area which proved to be lentigo maligna and she was referred to a dermato-oncology center. They have been given isotretinoin and physical sunscreen since then. The follow-up period was extended to 2 years and no serious complications occurred from the above treatment. This is an interesting report about XP in twins with the presentation of the rare neoplasm lentigo maligna.

PMID: 16971321 [PubMed - in process]

 

Ai Zheng. 2006 Sep;25(9):1113-9.

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[Correlation of XPC Ala499Val and Lys939Gln Polymorphisms to Risks of Esophageal Squamous Cell Carcinoma and Gastric Cardiac Adenocarcinoma.]

[Article in Chinese]

Zhou RM, Li Y, Wang N, Zhang XJ, Dong XJ, Guo W.

Laboratory of Molecular Biology, Hebei Provincial Cancer Institute, Shijiazhuang, Hebei, 050011,P. R. China.guoweiz2002@yahoo.com.cn.

BACKGROUND & OBJECTIVE: Xeroderma pigmentosum group C(XPC) gene is involved in nucleotide excision repair (NER). Single nucleotide polymorphisms (SNP) in XPC gene may affect DNA repairing capacity and genetic susceptibility to cancer. This study was to investigate the correlation of XPC exon 8 Ala499Val and exon 15 Lys939Gln SNPs to the susceptibility of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in a population at a high incidence region of Hebei Province. METHODS: XPC exon 8 Ala499Val and exon 15 Lys939Gln SNPs were genotyped by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis in 327 ESCC patients, 253 GCA patients, and 612 healthy controls. RESULTS: The number of the subjects with family history of upper gastrointestinal cancer (UGIC) was significantly higher in ESCC and GCA groups than in control group. Family history of UGIC may increase the risk of developing ESCC and GCA [age and gender adjusted odds ratio (OR) =1.76 and 1.77, 95% confidence interval (CI) = 1.34-2.32 and 1.31-2.39]. The overall allelotype and genotype distributions of XPC exon 8 Ala499Val in ESCC patients were not significantly different from those in healthy controls (P>0.05). T allelotype frequence of XPC exon 8 in GCA patients was 26.5%, which was significantly lower than that in healthy controls (Chi2=6.12, P=0.01). The C/T genotype frequencies of XPC exon 8 in GCA patients and healthy controls were 35.6% and 46.1% respectively. Compared with individuals with C/C genotype, individuals with C/T genotype had significantly lower risk in developing GCA (OR=0.62, 95% CI=0.45-0.84). When stratified for smoking status and family history of UGIC, compared with individuals with C/C genotype, individuals with C/T genotype in smoker group and in the group without family history of UGIC had lower risk in developing GCA (OR=0.57, 95% CI=0.36-0.91 and 0.37-0.88). The overall allelotype and genotype distributions of XPC exon 15 Lys939Gln in ESCC and GCA patients were not significantly different from those in healthy controls (P>0.05). When stratified for smoking status and family history of UGIC, compared with individuals with A/A genotype, individuals in non-smoker group with C/C genotype had higher risk in developing ESCC (OR=2.05, 95% CI=1.15-3.66). The haplotype distribution of ESCC patients was not significantly different from that of healthy controls (P>0.05), while the haplotype distribution of GCA patients was significantly different from that of healthy controls (P=0.02). Compared with A/T haplotype, A/C and C/C haplotypes significantly increased the risk of developing GCA (OR=1.35 and 1.46, 95% CI=1.01-1.81 and 1.06-2.00). CONCLUSIONS: In the high incidence region of Hebei Province, C/T genotype of XPC exon 8 may decrease the risk of developing GCA. Lys939Gln SNP in exon 15 may have no influence on the risk of ESCC and GCA, but when stratified for smoking status, C/C genotype of XPC exon 15 may increase the risk of developing ESCC in non-smoking population. While A/C and C/C haplotypes may increase the risk of developing GCA.

PMID: 16965652 [PubMed - in process]

 

Mutat Res. 2006 Sep 7; [Epub ahead of print]

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Role of nucleotide excision repair deficiency in intestinal tumorigenesis in multiple intestinal neoplasia (Min) mice.

Steffensen IL, Schut HA, Nesland JM, Tanaka K, Alexander J.

Department of Food Toxicology, Division of Environmental Medicine, Norwegian Institute of Public Health, NO-0403 Oslo, Norway.

Mice deficient in the Xeroderma pigmentosum group A (Xpa) gene are defective in nucleotide excision repair (NER) and highly susceptible to skin carcinogenesis after dermal exposure to UV light or chemicals. Min (multiple intestinal neoplasia) mice, heterozygous for a germline nonsense mutation in the tumor suppressor gene adenomatous polyposis coli (Apc), develop intestinal tumors spontaneously and show additional intestinal tumors after exposure to the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In this study, we investigated the impact of loss of XPA function on PhIP-induced intestinal tumorigenesis in F1 offspring of Min/+ (Apc(+/-)) mice crossed with Xpa gene-deficient mice. Apc(+/-) mice lacking both alleles of Xpa had higher susceptibility towards toxicity of PhIP, higher levels of PhIP-DNA adducts in the middle and distal small intestines as well as in liver, and a higher number of small intestinal tumors at 11 weeks, compared with Apc(+/-) mice with one or two intact Xpa alleles. Localization of tumors was not affected, being highest in middle and distal small intestines in all genotypes. At 11 weeks of age, the number of spontaneous intestinal tumors was not significantly increased by homozygous loss of Xpa, but untreated Apc(+/-)/Xpa(-/-) mice had significantly shorter life-spans than their XPA-proficient littermates. Heterozygous loss of Xpa did not affect any of the measured end points. In conclusion, the Xpa gene and the NER pathway are involved in repair of bulky PhIP-DNA adducts in the intestines and the liver, and most probably of DNA lesions leading to spontaneous intestinal tumors. These results confirm a role of the NER pathway also in protection against cancer in internal organs, additional to its well-known importance in protection against skin cancer. An effect of Apc(+/-) on adduct levels, additional to that of Xpa(-/-), indicates that the truncated APC protein may affect a repair pathway other than NER.

PMID: 16962818 [PubMed - as supplied by publisher]

 

Mutat Res. 2006 Jul 25;599(1-2):124-34. Epub 2006 Mar 27.

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Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study.

Dianzani I, Gibello L, Biava A, Giordano M, Bertolotti M, Betti M, Ferrante D, Guarrera S, Betta GP, Mirabelli D, Matullo G, Magnani C.

Laboratorio di Patologia Genetica, Dipartimento di Scienze Mediche, Universita del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy. irma.dianzani@med.unipmn.it

Differences in response to carcinogenic agents are due to the allelic variants of the genes that control it. Key genes are those involved in the repair of the DNA damage caused by such agents. This paper describes the results of a case-control epidemiological study designed to determine the genotypes of four of these genes in persons exposed to a single genotoxic factor, i.e. asbestos, who had or had not developed malignant mesothelioma (MM). Our working hypothesis was that an imperfect DNA repair, as revealed by subtle polymorphic variants, could reduce protection against the chronic DNA insult provoked by asbestos and eventually result in mutagenesis and cancer. Seven variants (i.e. XRCC1-R399Q-NCBI SNP, XRCC1-R194W, XRCC3-T241M, XRCC3-IVS6-14, XPD-K751Q, XPD-D312N, OGG1-S326C) were investigated in 81 patients and 110 age and sex-matched controls, all residents at Casale Monferrato, a Piedmontese town highly exposed to asbestos pollution. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). When considered as a categorical variable, XRCC1-399Q showed an increased OR both in heterozygotes (OR=2.08; 95% CI=1.00-4.33) and homozygotes (2.38; 95% CI=0.82-6.94), although individual ORs were not significant. When it was considered as a continuous variable OR was significant (OR=1.68; 95% CI: 1.02-2.75). When genotypes were divided into "non-risk" and "risk" genotypes, i.e. those thought to be associated with increased risk in the light of the functional significance of the variants, XRCC1-399Q (Q homozygotes+Q/R heterozygotes versus R homozygotes) had an OR=2.147 (95% CI: 1.08-4.28), whereas that of XRCC3-241T (T homozygotes+M/T heterozygotes versus M homozygotes) was 4.09 (95% CI: 1.26-13.21) and that of OGG1-326C was increased, though not significantly. None of the haplotypes showed a significantly different frequency between patients and controls. This is the first report of an association between polymorphisms in DNA repair genes and asbestos-associated MM. Our data indicate that genetic factors are involved in MM development.

PMID: 16564556 [PubMed - indexed for MEDLINE]

 

 

Br J Dermatol. 2006 Jul;155(1):81-8.

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A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma.

Sidwell RU, Sandison A, Wing J, Fawcett HD, Seet JE, Fisher C, Nardo T, Stefanini M, Lehmann AR, Cream JJ.

Histopathology, Charing Cross Hospital, London, U.K.

Background Xeroderma pigmentosum (XP) is an autosomal recessive disorder of, in most cases, defective nucleotide excision repair (NER) of ultraviolet radiation (UV)- and chemical-induced DNA damage. The condition is characterized by an increased sensitivity of the skin to UV radiation, with early development of pigmentary changes and premalignant lesions in sun-exposed areas of the skin, signs of photoageing and a greatly increased incidence from a young age of skin tumours including melanoma. Approximately 20% of patients with XP show neurological abnormalities of varying severity due to primary neuronal degeneration. Genetic analysis by somatic cell hybridization has led to the identification in the NER-defective form of XP of seven complementation groups, designated XP-A to XP-G. These complementation groups correspond to different proteins involved in the NER process. XP-A classically includes some of the most severely affected patients. Objectives We describe a 61-year-old Punjabi woman with XP. Remarkably she had only mild cutaneous abnormalities, minimal neurological features and unusual longevity, and developed a malignant spindle cell melanoma. There are few previous reports of spindle cell melanoma associated with XP. To gain insight into the aetiology of these unusual features, we sought to analyse the DNA repair properties of the patient and identify the complementation group and the causative mutation in the defective gene. Methods Unscheduled DNA synthesis and the inhibition of RNA synthesis were measured. The complementation group was assigned by fusing the cells of our patient with XP cells of known complementation groups and determining the ability to carry out unscheduled DNA repair. Molecular analysis of the cDNA was carried out by polymerase chain reaction and DNA sequencing. Results Levels of DNA repair were extremely low and complementation analysis assigned the defect to the XP-A group. Sequencing of the XPA gene revealed a novel homozygous mutation of A-->G at the eighth nucleotide of intron 4 causing aberrant splicing and a nonfunctional truncated XP-A protein. However, a small amount of normally spliced mRNA was detected at <5% the level in normal cells. Conclusions The small amount of normally spliced mRNA detected may be sufficient to explain the relatively mild clinical features in our patient.

PMID: 16792756 [PubMed - in process]

Mutat Res. 2006 Jun 10; [Epub ahead of print]

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Tissue specific mutagenic and carcinogenic responses in NER defective mouse models.

Wijnhoven SW, Hoogervorst EM, de Waard H, van der Horst GT, van Steeg H.

National Institute of Public Health and the Environment (RIVM), Laboratory of Toxicology, Pathology and Genetics, PO Box 1, 3720 BA, Bilthoven, The Netherlands.

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) are - except 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.

PMID: 16769089 [PubMed - as supplied by publisher]

Am J Epidemiol. 2006 May 17; [Epub ahead of print]

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XRCC3 and XPD/ERCC2 Single Nucleotide Polymorphisms and the Risk of Cancer: A HuGE Review.

Manuguerra M, Saletta F, Karagas MR, Berwick M, Veglia F, Vineis P, Matullo G.

Section of Epidemiology, ISI Foundation (Institute for Scientific Interchange), Torino, Italy.

Hundreds of polymorphisms in DNA repair genes have been identified; however, for many of these polymorphisms, the impact on repair phenotype and cancer susceptibility remains uncertain. In this review, the authors focused on the x-ray repair cross-complementing protein group 3 (XRCC3) and xeroderma pigmentosum group D (XPD)/excision repair cross-complementing rodent repair deficiency (ERCC2) genes, because they are among the most extensively studied but no final conclusion has yet been drawn about their role in cancer occurrence. XRCC3 participates in DNA double-strand break/recombinational repair through homologous recombination to maintain chromosome stability. XPD/ERCC2 is a helicase involved in the nucleotide excision repair pathway, which recognizes and repairs many structurally unrelated lesions, such as bulky adducts and thymidine dimers. The authors identified a sufficient number of epidemiologic studies on cancer to perform meta-analyses for XPD/ERCC2 variants in codons 156, 312, and 751 and XRCC3 variants in codon 241. The authors evaluated all cancer sites to investigate whether DNA repair is likely to take place in a rather nonspecific manner for different carcinogens and different cancers. For the most part, the authors found no association between these genes and the cancer sites investigated, except for some statistically significant associations between XPD/ERCC2 single nucleotide polymorphisms and skin, breast, and lung cancers.

PMID: 16707649 [PubMed - as supplied by publisher]

Cancer. 2006 Apr 28; [Epub ahead of print]

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Xeroderma pigmentosum group D haplotype predicts for response, survival, and toxicity after platinum-based chemotherapy in advanced nonsmall cell lung cancer.

Booton R, Ward T, Heighway J, Taylor P, Power F, Ashcroft L, Morris J, Thatcher N.

Christie Hospital National Health Service Trust, Manchester, United Kingdom.

BACKGROUND: The treatment of lung cancer has reached a therapeutic plateau. Several mechanisms of platinum resistance have been described, including the removal of platinum-DNA adduct by nucleotide excision repair (NER). Polymorphisms within the Xeroderma pigmentosum Group D protein (XPD), a member of the NER pathway, are associated with alterations in enzyme activity and may change sensitivity to platinum-based chemotherapy. The authors investigated the relation between XPD polymorphisms and treatment response, toxicity, and overall survival in patients who received platinum-based chemotherapy for advanced nonsmall cell lung cancer (NSCLC). METHODS: Between 2001 and 2002, 108 patients with chemotherapy-naive, advanced NSCLC were recruited. Associations between XPD312/751 polymorphisms and XPD haplotype and treatment response, toxicity. and survival were evaluated. RESULTS: Significant correlations were observed between XPD haplotype and Grade 4 neutropenia and overall survival together with a greater response to platinum-based chemotherapy for the XPD *A haplotype. CONCLUSIONS: The XPD haplotype may represent a useful pharmacogenomic marker of platinum-based chemotherapy in patients with advanced NSCLC and requires prospective validation. Cancer 2006. (c) 2006 American Cancer Society.

PMID: 16649224 [PubMed - as supplied by publisher]

Int J Cancer. 2006 Apr 27; [Epub ahead of print]

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Genetic polymorphisms of the XPG and XPD nucleotide excision repair genes in sarcoma patients.

Le Morvan V, Longy M, Bonaiti-Pellie C, Bui B, Houede N, Coindre JM , Robert J, Pourquier P.

Laboratory of Pharmacology of Anticancer Agents EA 515, Institut Bergonie & Universite Victor Segalen Bordeaux 2, Bordeaux, France.

There are more than 50 subtypes of soft tissue sarcomas, among which 30% are associated with specific genetic alterations, including translocations. Several studies have reported associations between cancer risk and polymorphisms of DNA repair genes from the nucleotide excision repair (NER) pathway. NER involves more than 20 proteins whose inactivation leads to xeroderma pigmentosum (XP) or cockayne syndrome (CS), among which XPD, a helicase allowing DNA strand excision by the endonuclease XPG. DNA from 93 patients with synovial sarcomas, myxoid liposarcomas, dermatofibrosarcomas protuberans (DFSP), malignant fibrous histiocytomas and leiomyosarcomas were genotyped for both XPD Lys751Gln and XPG Asp1104His polymorphisms. Departure from Hardy-Weinberg was highly significant for the XPG polymorphism with an excess of heterozygotes in synovial sarcomas (p = 1.5 x 10(-5)), myxoid liposarcomas (p = 1.5 x 10(-4)) and to a lesser extent in DFSP (p = 0.028). In the case of XPD, a significant deviation was observed in synovial sarcomas (p = 3 x 10(-6)) and DFSP (p = 0.0014). When tumors were pooled according to their genetic alterations, the proportion of carriers of the variant XPG allele was significantly increased in sarcomas with specific translocations as compared to sarcomas with complex genetics (p < 10(-9)). No difference was found for XPD. Genotyping of the tumor samples in synovial sarcomas and myxoid liposarcomas revealed frequent loss of heterozygosity for XPG, mostly due to the loss of the frequent allele. For XPD, both alleles were lost with a similar frequency. Our results raise the potential implication of the XPG Asp1104His polymorphism in the occurrence of chromosomal translocations associated with specific subtypes of sarcomas. (c) 2006 Wiley-Liss, Inc.

PMID: 16646069 [PubMed - as supplied by publisher]

Mol Cell. 2006 Apr 7;22(1):27-37.

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Conserved XPB Core Structure and Motifs for DNA Unwinding: Implications for Pathway Selection of Transcription or Excision Repair.

Fan L, Arvai AS, Cooper PK, Iwai S, Hanaoka F, Tainer JA.

Life Sciences Division, Department of Molecular Biology, Lawrence Berkeley National Laboratory, Berkeley, California 94720; Department of Molecular Biology, Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, California 92037.

The human xeroderma pigmentosum group B (XPB) helicase is essential for transcription, nucleotide excision repair, and TFIIH functional assembly. Here, we determined crystal structures of an Archaeoglobus fulgidus XPB homolog (AfXPB) that characterize two RecA-like XPB helicase domains and discover a DNA damage recognition domain (DRD), a unique RED motif, a flexible thumb motif (ThM), and implied conformational changes within a conserved functional core. RED motif mutations dramatically reduce helicase activity, and the DRD and ThM, which flank the RED motif, appear structurally as well as functionally analogous to the MutS mismatch recognition and DNA polymerase thumb domains. Substrate specificity is altered by DNA damage, such that AfXPB unwinds dsDNA with 3' extensions, but not blunt-ended dsDNA, unless it contains a lesion, as shown for CPD or (6-4) photoproducts. Together, these results provide an unexpected mechanism of DNA unwinding with implications for XPB damage verification in nucleotide excision repair.

PMID: 16600867 [PubMed - in process

Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4056-61. Epub 2006 Mar 6.

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Repair of DNA-polypeptide crosslinks by human excision nuclease.

Reardon JT, Sancar A.

Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.

DNA-protein crosslinks are relatively common DNA lesions that form during the physiological processing of DNA by replication and recombination proteins, b y side reactions of base excision repair enzymes, and by cellular exposure to bifunctional DNA-damaging agents such as platinum compounds. The mechanism by which pathological DNA-protein crosslinks are repaired in humans is not known. In this study, we investigated the mechanism of recognition and repair of protein-DNA and oligopeptide-DNA crosslinks by the human excision nuclease. Under our assay conditions, the human nucleotide excision repair system did not remove a 16-kDa protein crosslinked to DNA at a detectable level. However, 4- and 12-aa-long oligopeptides crosslinked to the DNA backbone were recognized by some of the damage recognition factors of the human excision nuclease with moderate selectivity and were excised from DNA at relatively efficient rates. Our data suggest that, if coupled with proteolytic degradation of the crosslinked protein, the human excision nuclease may be the major enzyme system for eliminating protein-DNA crosslinks from the genome.

PMID: 16537484 [PubMed - indexed for MEDLINE]

J Biol Chem. 2006 Mar 8; [Epub ahead of print]

Books

Cullin 4A-mediated proteolysis of DDB2 protein at DNA damage sites regulates in vivo lesion recognition by XPC.

El-Mahdy MA, Zhu Q, Wang QE, Wani G, Praetorius-Ibba M, Wani AA.

Radiology/Medical Biochemistry, The Ohio State University, Columbus, OH 43210.

Xeroderma pigmentosum complement-ation group E gene product, damaged DNA binding protein 2, is a subunit of DDB heterodimeric protein complex with high specificity for binding to a variety of DNA helix-distorting lesions. DDB is believed to play a role in the initial step of damage recognition in mammalian nucleotide excision repair of ultraviolet light-induced photolesions. It has been shown that DDB2 is rapidly degraded after cellular UV irradiation. However, the relevance of DDB2 degradation to its functionality in NER is still unknown. Here, we provide evidence that Cullin 4A, a key component of CUL-4A-based ubiquitin ligase, mediates DDB2 degradation at the damage sites and regulates the recruitment of XPC and the repair of cyclobutane pyrimidine dimers. We show that CUL-4A can be identified in an UV-responsive protein complex containing both DDB subunits. CUL-4A was visualized in localized UV-irradiated sites together with DDB2 and XPC. Degradation of DDB2 could be blocked by silencing CUL-4A using siRNA or by treating cells with proteasome inhibitor MG132. This blockage resulted in prolonged retention of DDB2 at the subnuclear DNA damage foci within micropore irradiated cells. Knockdown of CUL-4A also decreased recruitment of the damage recognition factor, XPC, to the damaged foci and concomitantly reduced the removal of CPD from the entire genome. These results suggest that CUL-4A mediates the proteolytic degradation of DDB2 and that this degradation event, initiated at the lesion sites, regulates damage recognition by XPC during the early steps of NER.

PMID: 16527807 [PubMed - as supplied by publisher]

Carcinogenesis. 2006 Mar 7; [Epub ahead of print]

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Polymorphisms in DNA damage binding protein 2 (DDB2) and susceptibility of primary lung cancer in Chinese: a case-control study.

Hu Z, Shao M

, Yuan J, Xu L, Wang F, Wang Y, Yuan W, Qian J, Ma H, Wang Y, Liu H, Chen W, Yang L, Jing G, Huo X, Chen F, Jin L, Wei Q, Huang W, Lu D, Wu T, Shen H.

Department of Epidemiology and Biostatistics, Cancer Research Center of Nanjing Medical University, Nanjing 210029, China.

DNA damage binding protein 2 (DDB2) is one of the major DNA repair proteins involved in the nucleotide excision repair (NER) pathway. Mutations in the DDB2 gene can cause a repair-deficiency syndrome xeroderma pigmentosum group E (XPE). Because tobacco carcinogens can cause DNA damage that is repaired by NER and suboptimal NER capacity is reported to be associated with lung cancer risk, we hypothesized that common variants in the DDB2 gene are associated with lung cancer risk. To test this hypothesis, we conducted a case-control study of 1010 patients with incident lung cancer and 1011 cancer-free controls and genotyped two DDB2 single nucleotide polymorphisms (SNPs) (rs830083 and rs3781620) that are in linkage disequilibrium with other untyped SNPs. We found that compared with the rs830083CC, subjects carrying the heterozygous rs830083CG genotype had a significantly 1.31-fold increased risk of lung cancer (95% CI 1.08-1.60) and those carrying the homozygous rs830083GG genotype had a non-significantly 1.22-fold elevated risk (95% CI 0.89-1.67). In addition, effects of the combined rs830083CG/GG variant genotypes were more evident in young subjects, heavy smokers, and subjects with a positive family history of cancer. These findings indicate, for the first time, that the DDB2 rs830083 polymorphism may contribute to the etiology of lung cancer. Further functional studies on this SNP and/or related variants are warranted to elucidate the underlying molecular mechanisms of the association.

PMID: 16522664 [PubMed - as supplied by publisher]

DNA Repair (Amst). 2006 Mar 4; [Epub ahead of print]

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UV-induced RPA phosphorylation is increased in the absence of DNA polymerase eta and requires DNA-PK.

Cruet-Hennequart S, Coyne S, Glynn MT, Oakley GG, Carty MP.

DNA Damage Response Laboratory, Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Galway City, Ireland.

Signaling from arrested replication forks plays a role in maintaining genome stability. We have investigated this process in xeroderma pigmentosum variant cells that carry a mutation in the POLH gene and lack functional DNA polymerase eta (poleta). Poleta is required for error-free bypass of UV-induced cyclobutane pyrimidine dimers; in the absence of poleta in XPV cells, DNA replication is arrested at sites of UV-induced DNA damage, and mutagenic bypass of lesions is ultimately carried out by other, error-prone, DNA polymerases. The present study investigates whether poleta expression influences the activation of a number of UV-induced DNA damage responses. In a stably transfected XPV cell line (TR30-9) in which active poleta can be induced by addition of tetracycline, expression of poleta determines the extent of DNA double-strand break formation following UV-irradiation. UV-induced phosphorylation of replication protein A (RPA), a key DNA-binding protein involved in DNA replication, repair and recombination, is increased in cells lacking poleta compared to when poleta is expressed in the same cell line. To identify the protein kinase responsible for increased UV-induced hyperphosphorylation of the p34 subunit of RPA, we have used NU7441, a specific small molecule inhibitor of DNA-PK. DNA-PK is necessary for RPA p34 hyperphosphorylation, but DNA-PK-mediated phosphorylation is not required for recruitment of RPA p34 into nuclear foci in response to UV-irradiation. The results demonstrate that activation of a UV-induced DNA damage response pathway, involving phosphorylation of RPA p34 by DNA-PK, is enhanced in cells lacking poleta.

PMID: 16520097 [PubMed - as supplied by publisher]

J Immunol. 2006 Mar 1;176(5):2896-901.

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IL-18 reduces ultraviolet radiation-induced DNA damage and thereby affects photoimmunosuppression.

Schwarz A, Maeda A, Stander S, van Steeg H, Schwarz T.

Department of Dermatology, University Kiel, Kiel, Germany.

UV-induced DNA damage has been recognized as the major molecular trigger for photoimmunosuppression. IL-12 prevents UV-induced immunosuppression via its recently discovered capacity to reduce DNA damage presumably via induction of DNA repair. Because IL-18 shares some biological activities with IL-12 we studied the effect of IL-18 on UV-induced DNA damage and immunosuppression. IL-18 reduced UV-induced apoptosis of keratinocytes and supported long-term cell survival on UV exposure. Injection of IL-18 into mice that were exposed to UV radiation significantly lowered the number of apoptotic keratinocytes. Accordingly, radiation immunohistochemistry revealed reduced amounts of DNA damage in epidermal cells upon injection of IL-18. These effects were not observed in DNA repair-deficient (XpaKO) mice, indicating that IL-18 like IL-12 reduces DNA damage via DNA repair. UV-mediated suppression of the induction of contact hypersensitivity, which is known to be primarily triggered by DNA damage, was prevented upon injection of IL-18 before UV exposure in wild-type but not in XpaKO mice. In contrast to IL-12, IL-18 was not able either in wild-type or in XpaKO mice to break UV-induced immunotolerance that is mediated via regulatory T cells rather than in a DNA damage-dependent fashion. This result indicates that IL-12 is still unique in its capacity to restore immune responses because of its effect on regulatory T cells. Together, these data identify IL-18 as a further cytokine that exhibits the capacity to affect DNA repair. Though being primarily a proinflammatory cytokine through this capacity, IL-18 can also foster an immune response that is suppressed by UV radiation.

PMID: 16493047 [PubMed - indexed for MEDLINE]

Proc Natl Acad Sci U S A. 2006 Feb 10; [Epub ahead of print]

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The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites.

Kapetanaki MG, Guerrero-Santoro J

, Bisi DC, Hsieh CL, Rapic-Otrin V, Levine AS.

Department of Molecular Genetics and Biochemistry, School of Medicine, and Cancer Institute, University of Pittsburgh, Hillman Cancer Center, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213.

Xeroderma pigmentosum (XP) is a heritable human disorder characterized by defects in nucleotide excision repair (NER) and the development of skin cancer. Cells from XP group E (XP-E) patients have a defect in the UV-damaged DNA-binding protein complex (UV-DDB), involved in the damage recognition step of NER. UV-DDB comprises two subunits, products of the DDB1 and DDB2 genes, respectively. Mutations in the DDB2 gene account for the underlying defect in XP-E. The UV-DDB complex is a component of the newly identified cullin 4A-based ubiquitin E3 ligase, DDB1-CUL4A(DDB2). The E3 ubiquitin ligases recognize specific substrates and mediate their ubiquitination to regulate protein activity or target proteins for degradation by the proteasomal pathway. In this study, we have addressed the role of the UV-DDB-based E3 in NER and sought a physiological substrate. We demonstrate that monoubiquitinated histone H2A in native chromatin coimmunoprecipitates with the endogenous DDB1-CUL4A(DDB2) complex in response to UV irradiation. Further, mutations in DDB2 alter the formation and binding activity of the DDB1-CUL4A(DDB2) ligase, accompanied by impaired monoubiquitination of H2A after UV treatment of XP-E cells, compared with repair-proficient cells. This finding indicates that DDB2, as the substrate receptor of the DDB1-CUL4A-based ligase, specifically targets histone H2A for monoubiquitination in a photolesion-binding-dependent manner. Given that the loss of monoubiquitinated histone H2A at the sites of UV-damaged DNA is associated with decreased global genome repair in XP-E cells, this study suggests that histone modification, mediated by the XPE factor, facilitates the initiation of NER.

PMID: 16473935 [PubMed - as supplied by publisher]

Birth Defects Res A Clin Mol Teratol. 2006 Feb 9;76(2):129-132 [Epub ahead of print]

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Neural tube development requires the cooperation of p53- and Gadd45a-associated pathways.

Patterson AD, Hildesheim J, Fornace AJ Jr, Hollander MC.

National Institutes of Health-George Washington University Graduate Partnerships Program in Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

BACKGROUND: Numerous genetically engineered mouse models for neural tube defects (NTDs) exist, and some of the implicated proteins are functionally related. For example, the growth arrest and DNA damage-inducible protein Gadd45a and tumor suppressor p53 are functionally similar, and both are involved in neural tube development (Gadd45a- and Trp53-null embryos show low levels of exencephaly). To assess their roles in neural tube development, we generated double-null mice from Gadd45a- and Trp53-null mice, as well as from cyclin-dependent kinase inhibitor (Cdkn1a) (p21)-null and xeroderma pigmentosum group C (XPC)-null mice that do not show spontaneous exencephaly. METHODS: Gadd45a-, Trp53-, Cdkn1a-, and XPC-null mice were crossed to generate several double-null mouse models. Embryos (embryonic day [ED] 16-18) from the single- and double-null crosses were scored for NTDs. RESULTS: Deletion of both Gadd45a and Trp53 in mice increased exencephaly frequencies compared to the deletion of either single gene (34.0% in Gadd45a/Trp53-null compared to 8.4% and 9.1% in the Gadd45a- and Trp53-null embryos, respectively). Furthermore, although deletion of another p53-regulated gene, Cdkn1a, is not associated with exencephaly, in conjunction with Gadd45a deletion, the exencephaly frequencies are increased (30.5% in the Gadd45a/Cdkn1a-null embryos) and are similar to those in the Gadd45a/Trp53-null embryos. Although XPC deletion increased exencephaly frequencies in Trp53-null embryos, XPC deletion did not increase the exencephaly frequencies in Gadd45a-null embryos. CONCLUSIONS: The increased genetic liability to exencephaly in the Gadd45a/Trp53- and Gadd45a/Cdkn1a-null embryos may be related to the disruption of multiple cellular pathways associated with Gadd45a and p53. Birth Defects Research (Part A), 2006. (c) 2006 Wiley-Liss, Inc.

PMID: 16470852 [PubMed - as supplied by publisher]

Transgenic Res. 2005 Dec;14(6):845-57.

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The Effect of DNA Repair Defects on Reproductive Performance in Nucleotide Excision Repair (NER) Mouse Models: An Epidemiological Approach.

Tsai PS, Nielen M, van der Horst GT, Colenbrander B, Heesterbeek JA, van Vlissingen JM.

Department of Farm Animal Health, Faculty of Veterinary Medi cine, Utrecht University, P.O. Box 80151, 3508, Utrecht, TD, The Netherlands.

In this study, we used an epidemiological approach to analyze an animal database of DNA repair deficient mice on reproductive performance in five Nucleotide Excision Repair (NER) mutant mouse models on a C57BL/6 genetic background, namely CSA, CSB, XPA, XPC [models for the human DNA repair disorders Cockayne Syndrome (CS) and xeroderma pigmentosum (XP), respectively] and mHR23B (not associated with human disease). This approach allowed us to detect and quantify reproductive effects based on a relatively small number of matings. We measured and quantified the scale of the effect between factors that might influence reproductive performance (i.e. age at co-housing, seasons) and reproductive parameters (i.e. litter size and pairing-to-birth interval -'pbi'). Besides, we detected and quantified the differences in reproductive performance between wild type mice and heterozygous/homozygous NER mutant mice. From our analyses, we found impaired reproduction in heterozygous and homozygous knock out mice; in particular, reduced litter size and lengthened pbi was related to the NER mutation-mHR23B, in heterozygous couples, even if they were otherwise phenotypically normal. Heterozygous mHR23B couples produced a 6.6-fold lower number of mHR23B(-/-) pups than indicated by Mendelian expectation; other genetic deficiencies studied were not statistically significant from each other or wild type controls. We concluded that careful epidemiological evaluations by analysis of animal database could provide reliable information on reproductive performance and detect deviations that would remain unnoticed without this. Also, some managerial aspects of mouse breeding could be evaluated.

PMID: 16315091 [PubMed - in process]

Science. 2005 Dec 16;310(5755):1821-4.

Books


Ubiquitin-binding domains in y-family polymerases regulate translesion synthesis.

Bienko M, Green CM, Crosetto N, Rudolf F, Zapart G, Coull B, Kannouche P, Wider G, Peter M, Lehmann AR, Hofmann K, Dikic I.

Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

Translesion synthesis (TLS) is the major pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage, ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of the lesion by directing the replication machinery into the TLS pathway. Yet, how this modification is recognized and interpreted in the cell remains unclear. Here we describe the identification of two ubiquitin (Ub)-binding domains (UBM and UBZ), which are evolutionarily conserved in all Y-family TLS polymerases (pols). These domains are required for binding of poleta and poliota to ubiquitin, their accumulation in replication factories, and their interaction with monoubiquitinated PCNA. Moreover, the UBZ domain of poleta is essential to efficiently restore a normal response to ultraviolet irradiation in xeroderma pigmentosum variant (XP-V) fibroblasts. Our results indicate that Ub-binding domains of Y-family polymerases play crucial regulatory roles in TLS.

PMID: 16357261 [PubMed - in process]

Pediatr Int. 2005 Dec;47(6):653-657.

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Primary malignant skin tumors in children: Etiology, treatment and prognosis.

Varan A, Gokoz A

, Akyuz C, Kutluk T, Yalcin B, Koksal Y, Buyukpamukcu M.

Department of Pediatric Oncology, Hacettepe University, Institute of Oncology, Ankara, Turkey.

Abstract Objective: The aim of the study was to evaluate the etiology, treatment and prognosis of the malignant skin tumors in children. Methods: Twenty-one patients who had been diagnosed with malignant skin tumors between 1972 and 2003 were retrospectively analyzed. Age range was 0.5-20 years (median 9), and the male/female ratio was 12/9. We had nine (42.9%) patients with malignant melanoma, five (23.8%) with primary skin non-Hodgkin lymphoma, three (14.3%) with Kaposi sarcoma (KS), two (9.5%) with basal cell carcinoma (BCC), and two (9.5%) with squamous cell carcinoma (SCC). Results: We could define the etiologic factors in only nine (42.9%) patients. Two KS cases were associated with renal transplantation, two cases of malignant melanoma occurred within the area of giant hairy cell nevus, one melanoma patient previously had bone marrow transplantation due to Gricelli syndrome, one patient with BCC had xeroderma pigmentosum and the other BCC had got radiotherapy due to previous diagnosis of medulloblastoma. One SCC patient also had xeroderma pigmentosum and the other had previous skin burn. Overall survival rate was 77%. Melanoma patients were treated successfully with high-dose interferon. Conclusion: Although malignant skin tumors are rare in childhood, the prognosis is relatively better than it is for adults. Malignant melanoma was the most frequent tumor. Forty-three per cent of our patients had an underlying defect in their immune barriers which is thought to be responsible for the development of their malignancies.

PMID: 16354219 [PubMed - as supplied by publisher]

Proc Natl Acad Sci U S A. 2005 Dec 12; [Epub ahead of print]

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Ubiquitinated proliferating cell nuclear antigen activates translesion DNA polymerases {eta} and REV1.

Garg P, Burgers PM.

Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110.

In response to DNA damage, the Rad6/Rad18 ubiquitin-conjugating complex monoubiquitinates the replication clamp proliferating cell nuclear antigen (PCNA) at Lys-164. Although ubiquitination of PCNA is recognized as an essential step in initiating postreplication repair, the mechanistic relevance of this modification has remained elusive. Here, we describe a robust in vitro system that ubiquitinates yeast PCNA specifically on Lys-164. Significantly, only those PCNA clamps that are appropriately loaded around effector DNA by its loader, replication factor C, are ubiquitinated. This observation suggests that, in vitro, only PCNA present at stalled replication forks is ubiquitinated. Ubiquitinated PCNA displays the same replicative functions as unmodified PCNA. These functions include loading onto DNA by replication factor C, as well as Okazaki fragment synthesis and maturation by the PCNA-coordinated actions of DNA polymerase delta, the flap endonuclease FEN1, and DNA ligase I. However, whereas the activity of DNA polymerase zeta remains unaffected by ubiquitination of PCNA, ubiquitinated PCNA specifically activates two key enzymes in translesion synthesis: DNA polymerase eta, the yeast Xeroderma pigmentosum ortholog, and Rev1, a deoxycytidyl transferase that functions in organizing the mutagenic DNA replication machinery. We propose that ubiquitination of PCNA increases its functionality as a sliding clamp to promote mutagenic DNA replication.

PMID: 16344468 [PubMed - as supplied by publisher]

Mol Cell. 2005 Dec 9;20(5):793-9.

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Dual Roles for DNA Polymerase eta in Homologous DNA Recombination and Translesion DNA Synthesis.

Kawamoto T, Araki K

, Sonoda E, Yamashita YM, Harada K, Kikuchi K, Masutani C, Hanaoka F, Nozaki K, Hashimoto N, Takeda S.

CREST, Japan Science and Technology Agency, Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan.

Chicken B lymphocyte precursors and DT 40 cells diversify their immunoglobulin-variable (IgV) genes through homologous recombination (HR)-mediated Ig gene conversion. To identify DNA polymerases that are involved in Ig gene conversion, we created DT40 clones deficient in DNA polymerase eta (poleta), which, in humans, is defective in the variant form of xeroderma pigmentosum (XP-V). Poleta is an error-prone translesion DNA synthesis polymerase that can bypass UV damage-induced lesions and is involved in IgV hypermutation. Like XP-V cells, poleta-disrupted (poleta) clones exhibited hypersensitivity to UV. Remarkably, poleta cells showed a significant decrease in the frequency of both Ig gene conversion and double-strand break-induced HR when compared to wild-type cells, and these defects were reversed by complementation with human poleta. Our findings identify a DNA polymerase that carries out DNA synthesis for physiological HR and provides evidence that a single DNA polymerase can play multiple cellular roles.

PMID: 16337602 [PubMed - in process]

Gan To Kagaku Ryoho. 2005 Nov;32(12):1895-901.

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[Genetic alterations and chemoresistance]

[Article in Japanese]

Akiyama S.

Dept. of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics, Graduate School of Medical and Dental Sciences, Kagoshima University.

Molecular targeting agents will likely play an increasing role in the management of cancer.However, resistance to anti-neoplastic drugs remains a serious obstacle to successful cancer treatment. Analysis of SNPs and microarray technologies should enable us to predict toxic responses and sensitivities to anticancer agents of each patient, and the prediction may permit patient-specific anticancer agents and dosages that reduce the risk of acute toxicity and emergence of drug-resistant tumors. The relationships are reviewed between the chemoresistance(chemosensitivity) and polymorphisms, tumor gene expression profiles or mutations of targeted molecules that confer resistance to molecular target therapy.

Publication Types:

Review


PMID: 16282723 [PubMed - indexed for MEDLINE]

Actas Dermosifiliogr. 2005 Nov;96(9):586-8.

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[De Sanctis-Cacchione syndrome]

[Article in Spanish]

Roson E, Garcia-Doval I, de la Torre C, Feal C, Cruces M.

Servicio de Dermatologia, Hospital Provincial, Complejo Hospitalario de Pontevedra, Spain. eroson64@yahoo.es

We present a male patient with photosensitivity since the earliest months of his life, and pigmented macules in exposed areas, some showing clinical atypia, which increased in number over time. Molecular biology studies detected an alteration in DNA repair ability, so xeroderma pigmentosum was diagnosed. Shortly after birth, low weight, microcephaly and psychomotor retardation had been observed, but the cause was not established. The patient progressively showed neurological disorders that included perceptive deafness, hyporeflexia and areflexia, as well as choreoathetotic movements. Therefore, we felt that the patient's symptoms fit De Sanctis-Cacchione syndrome.

PMID: 16476302 [PubMed - in process]