Molecular Analysis of DNA Polymerase Eta Gene in Japanese Patients Diagnosed as Xeroderma Pigmentosum Variant Type.

Tanioka M, Masaki T, Ono R, Nagano T, Otoshi-Honda E, Matsumura Y, Takigawa M, Inui H, Miyachi Y, Moriwaki S, Nishigori C.

[1] 1Department of Dermatology, Graduate School of Medicine, Kobe University, Kobe, Japan [2] 2Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

POLH mutations were identified in 16 Japanese patients, who were diagnosed, both clinically and at a cellular level, as being of the xeroderma pigmentosum variant type (XPV). While all the patients developed skin cancer with an average onset of the cancer at 45 years, in non-XP Japanese the onset was at over 70 years. All the cell strains from the patients were normal or slightly hypersensitive to UV and most of these showed enhanced UV sensitivity when the post-UV colony formation was performed in the presence of caffeine. Immunoprecipitation analysis with two kinds of anti-POLH protein antibodies revealed that cells from 13 patients did not show the 83 kDa POLH band and that cells from one patient had a faint 83 kDa band. All of these 14 cell strains, without a POLH band or with a weak POLH band, had mutations in the POLH gene. The IP analysis of the POLH protein revealed a very useful method for screening the patients suspected of XPV. Seven mutations in the POLH gene including three novel mutations were identified. Among the mutations detected, 11 alleles out of 28 (39%) were G490T mutations.Journal of Investigative Dermatology advance online publication, 8 March 2007; doi:10.1038/sj.jid.5700759.

PMID: 17344931 [PubMed - as supplied by publisher]





173421922: Nat Clin Pract Neurol. 2007 Mar;3(3):162-72.

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Mechanisms of disease: DNA repair defects and neurological disease.

Subba Rao K.

Indian Council of Medical Research Centre for Research on Aging and Brain, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India.

In this Review, familial and sporadic neurological disorders reported to have an etiological link with DNA repair defects are discussed, with special emphasis placed on the molecular link between the disease phenotype and the precise DNA repair defect. Of the 15 neurological disorders listed, some of which have symptoms of progeria, six--spinocerebellar ataxia with axonal neuropathy-1, Huntington's disease, Alzheimer's disease, Parkinson's disease, Down syndrome and amyotrophic lateral sclerosis--seem to result from increased oxidative stress, and the inability of the base excision repair pathway to handle the damage to DNA that this induces. Five of the conditions (xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Down syndrome, and triple-A syndrome) display a defect in the nucleotide excision repair pathway, four (Huntington's disease, various spinocerebellar ataxias, Friedreich's ataxia and myotonic dystrophy types 1 and 2) exhibit an unusual expansion of repeat sequences in DNA, and four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimer's disease) exhibit defects in genes involved in repairing double-strand breaks. The current overall picture indicates that oxidative stress is a major causative factor in genomic instability in the brain, and that the nature of the resulting neurological phenotype depends on the pathway through which the instability is normally repaired.

PMID: 17342192 [PubMed - in process]





173346343: Int J Mol Med. 2007 Apr;19(4):589-96.

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The human POLH gene is not mutated, and is expressed in a cohort of patients with basal or squamous cell carcinoma of the skin.

Flanagan AM, Rafferty G, O'neill A, Rynne L, Kell y J, McCann J, Carty MP.

Department of Biochemistry, National University of Ireland, Galway, Ireland.

Skin cancer, the most common cancer in the general population, is strongly associated with exposure to the ultraviolet component of sunlight. To investigate the relationship between DNA damage processing and skin tumour development, we determined the POLH status of a cohort of skin cancer patients. The human POLH gene encodes DNA polymerase eta (poleta), which normally carries out accurate translesion synthesis past the major UV-induced photoproduct, the dithymine cyclobutane dimer. In the absence of active poleta in xeroderma pigmentosum variant (XPV) patients, mutations accumulate at sites of UV-induced DNA damage, providing the initiating step in skin carcinogenesis. Forty patients diagnosed with skin cancer were genotyped for polymorphisms in the POLH protein-coding sequence, using glycosylase-mediated polymorphism detection (GMPD) and direct DNA sequencing of POLH PCR products derived from white blood cell genomic DNA. All individuals carried the wild-type POLH sequence. No POLH mutations were identified in genomic DNA from skin tumours derived from 15 of these patients. As determined by RT-PCR, POLH mRNA was expressed in all normal and skin tumour tissue examined. Poleta protein was also detectable by Western blotting, in two matched normal and skin tumour extracts. An alternatively spliced form of POLH mRNA, lacking exon 2, was more readily detected in skin tissue than in white blood cells from the same patient. Real-time PCR was used to quantify POLH expression in matched normal and skin tumour-derived mRNA from a series of patients diagnosed with either basal or squamous cell carcinoma. Compared to matched normal skin tissue from the same patient, 1 of 7 SCC, and 4 of 10 BCC tumours examined showed at least a 2-fold reduction in POLH expression, while 1 of 7 SCC, and 3 of 10 BCC tumours showed at least a 2-fold increase in POLH expression. Differences in gene expression, rather than sequence changes may be the main mechanism by which POLH status varies between normal and skin tumours in the population under investigation. Knowledge of the POLH status in skin tumours could contribute to an understanding of the role of this gene in the development of the most common cancer in the general population.

PMID: 17334634 [PubMed - in process]






New areas of focus at workshop on human diseases involving DNA repair deficiency and premature aging.

Kraemer KH, Sander M, Bohr VA.

Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

Researchers and clinicians interested in human diseases of DNA repair deficiency and premature aging gathered at the National Conference Center in Lansdowne, Virginia on 5-8 September 2006 to attend a workshop co-organized by Vilhelm Bohr (National Institute of Aging) and Kenneth Kraemer (National Cancer Institute). An important feature of this workshop was the participation of representatives from xeroderma pigmentosum (XP), Cockayne Syndrome (CS) and trichothiodystrophy (TTD) family support groups. Studies presented at the workshop described important new insights into the phenotypic complexity of XP, CS and TTD, renewed focus on the neurological manifestations of each of these diseases, as well as keen interest in the role of oxidative stress and mitochondrial dysfunction in neurodegenerative processes and normal and/or premature aging. This workshop report summarizes some of the presentations and outcomes of the workshop.

Publication Types:

Clinical Conference


PMID: 17361460 [PubMed - in process]





173551812: PLoS Biol. 2007 Mar 13;5(4):e79 [Epub ahead of print]

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An Aromatic Sensor with Aversion to Damaged Strands Confers Versatility to DNA Repair.

Maillard O, Solyom S, Naegeli H.

It was not known how xeroderma pigmentosum group C (XPC) protein, the primary initiator of global nucleotide excision repair, achieves its outstanding substrate versatility. Here, we analyzed the molecular pathology of a unique Trp690Ser substitution, which is the only reported missense mutation in xeroderma patients mapping to the evolutionary conserved region of XPC protein. The function of this critical residue and neighboring conserved aromatics was tested by site-directed mutagenesis followed by screening for excision activity and DNA binding. This comparison demonstrated that Trp690 and Phe733 drive the preferential recruitment of XPC protein to repair substrates by mediating an exquisite affinity for single-stranded sites. Such a dual deployment of aromatic side chains is the distinctive feature of functional oligonucleotide/oligosaccharide-binding folds and, indeed, sequence homologies with replication protein A and breast cancer susceptibility 2 protein indicate that XPC displays a monomeric variant of this recurrent interaction motif. An aversion to associate with damaged oligonucleotides implies that XPC protein avoids direct contacts with base adducts. These results reveal for the first time, to our knowledge, an entirely inverted mechanism of substrate recognition that relies on the detection of single-stranded configurations in the undamaged complementary sequence of the double helix.

PMID: 17355181 [PubMed - as supplied by publisher]





171313453: Int J Cancer. 2007 Mar 1;120(5):1036-45.

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Polymorphisms in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple myeloma patients undergoing autologous bone marrow transplantation.

Vangsted A, Gimsing P, Klausen TW, Nexo BA, Wallin H, Andersen P, Hokland P, Lillevang ST, Vogel U.

Department of Haematology, Herlev University Hospital of Copenhagen, DK-2730 Herlev, Denmark.

Individual variations in the ability to cope with DNA damage by DNA repair may be essential for the response to chemotherapy, since cancer cells from patients with an effective DNA repair may survive treatment. We have studied the effect on time to treatment failure (TTF) and overall survival (OS) of polymorphism in the DNA repair genes ERCC1, ERCC2 and XRCC3, and in the apoptotic genes PPP1R13L and CD3EAP in 348 patients with multiple myeloma undergoing autologous bone marrow transplantation. Carriers of the variant C-allele of ERCC2 K751Q, the variant T-allele of XRCC3 T241M and the variant A-allele of CD3EAP G-21A had a 1.3-fold, 1.8-fold and 1.9-fold longer TTF, respectively, than homozygous wild type carriers (p = 0.006, p = 0.004, p < 0.001). The polymorphism CD3EAP G-21A also had significant effect on OS (p < 0.045). The polymorphism ERCC2 K751Q may to be related to sex, since the prolonged TTF was only seen in women (p = 0.001). Carriers of the combination of variant alleles of ERCC2 K751Q and XRCC3 T241M had 2.8-fold longer TTF (p = 0.0002).This indicates that suboptimal repair of both DNA mechanisms favors prolonged TTF and that polymorphism in ERCC2, XRCC3 and CD3EAP predicts the outcome for patients treated with autologous stem cell transplantation. Copyright 2006 Wiley-Liss, Inc.

Publication Types:

Multicenter Study

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



PMID: 17131345 [PubMed - indexed for MEDLINE]







173786881: Pediatr Dev Pathol. 2007 Mar-Apr;10(2):149-52.

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Atypical fibroxanthoma and squamous cell carcinoma of the conjunctiva in xeroderma pigmentosum.

Shao L, Newell B, Quintanilla N.

Patients with xeroderma pigmentosum (XP) have defective DNA repair and a high predisposition to developing abnormalities and neoplasia in the sun-exposed areas of the skin and mucous membranes. The most common tumors reported in patients with XP are squamous cell carcinomas, basal cell carcinomas, and melanomas. Atypical fibroxanthoma (AFX) is a pleomorphic tumor that arises predominantly in the sun-damaged skin of the head and neck regions of the elderly. We describe a unique case of a 6-year-old African American boy with XP who developed an atypical fibroxanthoma and 2 squamous cell carcinomas in the conjunctiva. The clinical and histopathologic findings of AFX are discussed.

PMID: 17378688 [PubMed - in process]





173749672: Pathobiology. 2006;73(6):295-303.

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Association between DNA Repair Gene Polymorphisms and p53 Alterations in Japanese Patients with Muscle-Invasive Bladder Cancer.

Sakano S, Matsumoto H, Yamamoto Y, Kawai Y, Eguchi S, Ohmi C, Matsuyama H, Naito K.

Department of Urology, Yamaguchi University School of Medicine, Ube, Japan .

Objective: DNA repair enzymes play a vital role in protecting the genome from carcinogens, several of which can cause mutations in the TP53 gene in bladder cancer. Some single nucleotide polymorphisms (SNPs) in DNA repair genes reportedly modulate the repair capacity. This study aimed to clarify the effect of these functional SNPs on the alteration of p53 in muscle-invasive bladder cancer. Methods: We investigated the association between SNPs in xeroderma pigmentosum complementation groups C (XPC), D and G and X-ray repair cross-complementing group 1 and 3 genes, and p53 expression and allelic imbalance at the TP53 locus in Japanese patients with muscle-invasive bladder cancer. p53 expression and the allelic imbalance were evaluated using immunohistochemistry and a microsatellite marker, respectively. Results: Positive p53 expression was significantly less frequent in patients with the CC genotype of the XPC gene than in those with the AA or AC genotype (p = 0.0005). C alleles of the XPC gene were also less frequent in patients with positive p53 expression (p = 0.01). Conclusion: Our results suggested that the XPC polymorphism might affect p53 alteration and the molecular pathway defined by the p53 alteration in the development of muscle-invasive bladder cancer. Copyright (c) 2006 S. Karger AG, Basel.

PMID: 17374967 [PubMed - in process]





173731893: J Drugs Dermatol. 2007 Mar;6(3):281-8.

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Xeroderma pigmentosum: beyond skin cancer.

Lichon V, Amor K.

University of Illinois, Chicago, IL, USA.

Xeroderma pigmentosum (XP) is a rare, autosomal-recessive inherited disease that is found worldwide at a frequency of approximately 1:250,000. XP is caused by a deficiency in either nucleotide excision repair (NER) or postreplication repair (PRR), and is characterized by severe actinic changes leading to early onset of skin cancers, various ocular manifestations, and occasional neurological abnormalities. Diagnosis is usually made clinically and can be confirmed by unscheduled DNA synthesis. Early preventative care is the most important treatment modality. We present a review of the history, clinical manifestations, pathogenesis, diagnosis, and treatment of XP.

PMID: 17373189 [PubMed - in process]






174414551: Masui. 2007 Apr;56(4):439-41.

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[Anesthesia for a patient with xeroderma pigmentosum]

[Article in Japanese]

Miyazaki R, Nagata T, Kai T, Takahashi S.

Department of Anesthesiology and Critical Care Medicine, Kyushu University Hospital, Fukuoka.

A 23-year-old man with xeroderma pigmentosum underwent laparoscopic cholecystectomy. He experienced transient worsening of the neurological symptom after anesthesia with volatile agents in the previous surgery. Because volatile anesthetics potentially cause genotoxic effects in patients with xeroderma pigmentosum, this time we chose total ir.travenous anesthesia (TIVA). The intraoperative management and the post-operative course were uneventful this time. From these two anesthesia experiences in one patient, we suggest that TIVA is more appropriate than anesthesia with volatile agents as a method for general anesthesia for xeroderma pigmentosum patients. Minimum usage of muscle relaxants under the monitoring of neuromuscular blockade is also recommended, since xeroderma pigmentosum patients are sensitive to muscle relaxants due to the neuronal dysfunction and muscle

Publication Types:

English Abstract


PMID: 17441455 [PubMed - in process]





173267242: PLoS Biol. 2006 Dec 12;5(1):e2.

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Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.

van der Pluijm I, Garinis GA, Brandt RM, Gorgels TG, Wijnhoven SW, Diderich KE, de Wit J, Mitchell JR, van Oostrom C, Beems R, Niedernhofer LJ, Velasco S, Friedberg EC, Tanaka K, van Steeg H, Hoeijmakers JH, van der Horst GT.

Department of Gen etics, Center for Biomedical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.

Publication Types:

Research Support, N.I.H., Extramural

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



PMID: 17326724 [PubMed - indexed for MEDLINE]





174762811: Leukemia. 2007 May 3; [Epub ahead of print]

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Role of MTHFR (677, 1298) haplotype in the risk of developing secondary leukemia after treatment of breast cancer and hematological malignancies.

Guillem VM, Collado M, Terol MJ, Calasanz MJ, Esteve J, Gonzalez M, Sanzo C, Nomdedeu J, Bolufer P, Lluch A, Tormo M.

1Servicio de Hematologia y Oncologia, Hospital Clinico Universitario de Valencia, Universidad de Valencia, Valencia, Spain.

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) is a malignancy occurring after exposure to chemotherapy and/or radiotherapy. Polymorphisms involved in chemotherapy/radiotherapy response genes could be related to an increased risk of developing this neoplasia. We have studied 11 polymorphisms in genes of drug detoxification pathways (NQO1, glutathione S-transferase pi) and DNA repair xeroderma pigmentosum, complementation group (3) (XPC(3), X-ray repair cross complementing protein (1)), Nijmegen breakage syndrome (1), excision repair cross-complementing rodent repair deficiency, complementation group (5) and X-ray repair cross complementing protein (3) and in the methylene tetrahydrofolate reductase gene (MTHFR(2), 677C>T, 1298A>C), involved in DNA synthesis. The analyzed groups were a t-MDS/AML patients group (n=81) and a matched control group (n=64) treated similarly, and they did not develop t-MDS/AML. We found no significant differences when the groups were compared globally. However, when analysis was carried out according to the primary neoplasia involved, a significant association was observed between the MTHFR haplotype (single nucleotide polymorphisms 677 and 1298) and the risk of developing t-MDS/AML in the breast cancer patients group (P=0.016) and cyclophosphamide-treated hematological disease group (P=0.005). Risk haplotype was different for each case, corresponding to the 677T1298A haplotype after breast cancer treatment and the 677C1298C haplotype after hematological malignancy treatment. We postulate that such differences are related to variations in chemotherapy schemes between hematological and breast cancers and their differential interaction with the MTHFR route.Leukemia advance online publication, 3 May 2007; doi:10.1038/sj.leu.2404709.

PMID: 17476281 [PubMed - as supplied by publisher]





174666262: Mol Cell. 2007 Apr 27;26(2):245-56.

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Distinct Roles for the XPB/p52 and XPD/p44 Subcomplexes of TFIIH in Damaged DNA Opening during Nucleotide Excision Repair.

Coin F, Oksenych V, Egly JM.

Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS (UMR7104)/INSERM (U596)/ULP, BP 163, 67404 Illkirch Cedex, C.U. Strasbourg, France.

Mutations in XPB, an essential subunit of the transcription/repair factor TFIIH, lead to nucleotide excision repair (NER) defects and xeroderma pigmentosum (XP). The role of XPB in NER and the molecular mechanisms resulting in XP are poorly understood. Here, we show that the p52 subunit of TFIIH interacts with XPB and stimulates its ATPase activity. A mutation found among XP-B patients (F99S) weakens this interaction and the resulting ATPase stimulation, thereby explaining the defect in the damaged DNA opening. We next found that mutations in the helicase motifs III (T469A) and VI (Q638A) that inhibit XPB helicase activity preserve the NER function of TFIIH. Our results suggest a mechanism in which the helicase activity of XPB is not used for the opening and repair of damaged DNA, which is instead only driven by its ATPase activity, in combination with the helicase activity of XPD.

PMID: 17466626 [PubMed - in process]





174666253: Mol Cell. 2007 Apr 27;26(2):231-43.

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XPG Stabilizes TFIIH, Allowing Transactivation of Nuclear Receptors: Implications for Cockayne Syndrome in XP-G/CS Patients.

Ito S, Kuraoka I, Chymkowitch P, Compe E, Takedachi A, Ishigami C, Coin F, Egly JM, Tanaka K.

Laboratories for Organismal Biosystems, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.

Mutations in the human XPG gene give rise to an inherited photosensitive disorder, xeroderma pigmentosum (XP) associated with Cockayne syndrome (XP-G/CS). The clinical features of CS in XP-G/CS patients are difficult to explain on the basis of a defect in nucleotide excision repair (NER). We found that XPG forms a stable complex with TFIIH, which is active in transcription and NER. Mutations in XPG found in XP-G/CS patient cells that prevent the association with TFIIH also resulted in the dissociation of CAK and XPD from the core TFIIH. As a consequence, the phosphorylation and transactivation of nuclear receptors were disturbed in XP-G/CS as well as xpg(-/-) MEF cells and could be restored by expression of wild-type XPG. These results provide an insight into the role of XPG in the stabilization of TFIIH and the regulation of gene expression and provide an explanation of some of the clinical features of XP-G/CS.

PMID: 17466625 [PubMed - in process]





174387034: Acta Oncol. 2007;46(1):31-41.

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Polymorphisms in XPD, XPC and the risk of death in patients with urinary bladder neoplasms.

Sanyal S, De Verdier PJ, Steineck G, Larsson P, Onelov E, Hemminki K, Kumar R.

Division of Clinical Cancer Epidemiology, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.

We conducted a follow-up study on 311 patients with urinary bladder neoplasms to investigate the association of polymorphisms in DNA repair and cell growth regulatory genes with the clinical outcomes of this disease. We found that patients carrying the variant allele of XPD (K751Q) polymorphism were at lower risk of death (p = 0.04) than the noncarriers. Patients that were simultaneous carriers of variant alleles from XPD (K751Q) and XPC (K939Q) polymorphisms, showed lower risk of death than the other patients (p = 0.001). The variant allele carriers of MSH6 (G39E) polymorphism showed a higher risk for highly malignant disease (TaG3 +T1) than the non-carriers (p = 0.03). The variant allele carriers of XRCC1 (R399Q) polymorphism showed lower risk for recurrence (TaG2; p = 0.05) and death (T2+; p = 0.03) after instillation and radiotherapy than the non-carriers. After radiotherapy, an inverse association of the variant allele of OGG1 (S326C) polymorphism was observed with the risk of death (T2 +; p = 0.04). A significant low-risk for stage progression (p = 0.03) was observed in patients carrying the variant allele of H-ras (H27H) polymorphism. Our results are consistent with the notion that the XPD (K751Q) polymorphism either individually or in combination with the XPC (K939Q) polymorphism modulates the risk of death in patients with urinary bladder neoplasms.

Publication Types:

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


PMID: 17438703 [PubMed - indexed for MEDLINE]





171184885: Lung Cancer. 2007 Mar;55(3):303-11. Epub 2006 Nov 21.

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Increased expression and activity of repair genes TDP1 and XPF in non-small cell lung cancer.

Liu C, Zhou S, Begum S, Sidransky D, Westra WH, Brock M, Califano JA.

Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Division, Johns Hopkins Medical Institutions, Baltimore, MD, United States.

Resistance to camptothecin (CPT), a topoisomerase I (Top1) inhibitor, is frequently encountered in non-small cell lung cancer ( NSCLC) and CPT resistance is linked with TDP1, an enzyme capable of cleaving the covalent linkage between stabilized Top1 with DNA. The aim of this study is to evaluate the in vivo expression level of TDP1, as well as parallel repair pathway components XPF and MUS81, in primary NSCLC. We collected 30 un-matched and 4 NSCLC samples matched with normal lung tissue and 8 samples of non-neoplastic lung tissue from patients with and without lung cancer, and determined the protein expression of these three genes using Western blot and TDP1 activity by a specific enzymatic assay. Both TDP1 and XPF were overexpressed in over 50% of NSCLC tissues, with wide ranges of expression levels. MUS81 did not exhibit alteration in expression. Overexpression of TDP1 and XPF is common in NSCLC, and is therefore of interest as a possible contributor to drug resistance in NSCLC.

Publication Types:

Research Support, N.I.H., Extramural

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



PMID: 17118488 [PubMed - indexed for MEDLINE]






175103961: Cancer Res. 2007 May 15;67(10):4695-9.


The combined effects of xeroderma pigmentosum C deficiency and mutagens on mutation rates in the mouse germ line.

Miccoli L, Burr KL, Hickenbotham P, Friedberg EC, Angulo J F, Dubrova YE.

Commissariat a l'Energie Atomique, Laboratoire de Genetique de la Radiosensibilite, Institut de Radiobiologie Cellulaire et Moleculaire, Direction des Sciences du Vivant, Fontenay aux Roses, France.

Spontaneous and induced mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germ line of xeroderma pigmentosum group C (Xpc) knockout mice defective in global genome nucleotide excision repair. Spontaneous and radiation-induced mutation rates in homozygous Xpc(-/-) males were significantly higher than those in isogenic wild-type (Xpc(+/+)) and heterozygous (Xpc(+/-)) mice. In contrast, exposure to the monofunctional alkylating agent ethylnitrosourea resulted in similar increases in ESTR mutation rates across all genotypes. ESTR mutation spectra in the germ line of Xpc(-/-), Xpc(+/-) and Xpc(+/+) did not differ. Considering these data and the results of other publications, we propose that the Xpc-deficient mice possess a mutator phenotype in their germ line and somatic tissues that may significantly enhance carcinogenesis across multiple tissues. [Cancer Res 2007;67(10):4695-9].

PMID: 17510396 [PubMed - in process]





175103832: Cancer Res. 2007 May 15;67(10):4578-85.


Attenuated expression of xeroderma pigmentosum group C is associated with critical events in human bladder cancer carcinogenesis and progression.

Chen Z, Yang J, Wang G, Song B, Li J, Xu Z.

Urology Institute of People's Liberation Army, Southwest Hospital, and Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing, P.R. China.

Xeroderma pigmentosum group C (XPC) is an important DNA damage recognition protein that binds to damaged DNA at a very early stage during DNA repair. The XPC protein is also involved in DNA damage-induced cell cycle checkpoint regulation and apoptosis. XPC defects are associated with many types of solid tumors. The mechanism of the XPC protein in cancer progression, however, remains unclear. In this report, we showed the strong correlation between bladder cancer progression and attenuated XPC protein expression using tissues derived from patients with bladder cancer. The results obtained from our immunohistochemical studies further revealed a strong correlation of XPC deficiency, p53 mutation, and the degree of malignancy of bladder tumors. In addition, the results obtained from our studies have also shown that HT1197 bladder cancer cells, which carry a low-level XPC protein, exhibited a decreased DNA repair capability and were resistant to cisplatin treatment. When an XPC gene cDNA-expression vector was stably transfected into the HT1197 cells, however, the cisplatin treatment-induced apoptotic cell death was increased. Increased p53 and p73 responses following cisplatin treatment were also observed in HT1197 cells stably transfected with XPC cDNA. Taken together, these results suggest that XPC deficiency is an important contributing factor in bladder tumor progression and bladder cancer cell drug resistance. [Cancer Res 2007;67(10):4578-85].

PMID: 17510383 [PubMed - in process]





175099503: DNA Repair (Amst). 2007 May 15; [Epub ahead of print]


Influence of XPB helicase on recruitment and redistribution of nucleotide excision repair proteins at sites of UV-induced DNA damage.

Oh KS, Imoto K, Boyle J, Khan SG, Kraemer KH.

Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

The XPB DNA helicase, a subunit of the basal transcription factor TFIIH, is also involved in nucleotide excision repair (NER). We examined recruitment of NER proteins in XP-B cells from patients with mild or severe xeroderma pigmentosum (XP) having different XPB mutations using local UV-irradiation through filters with 5mum pores combined with fluorescent antibody labeling. XPC was rapidly recruited to UV damage sites containing DNA photoproducts (cyclobutane pyrimidine dimers, CPD) in all the XP-B and normal cells, thus reflecting its role in damage recognition prior to the function of XPB. Cells from the mild XP-B patients, with a missense mutation, showed delayed recruitment of all NER proteins except XPC to UV damage sites, demonstrating that this mutation impaired localization of these proteins. Surprisingly, in cells from severely affected patients, with a C-terminal XPB mutation, XPG and XPA proteins were normally recruited to UV damage sites demonstrating that this mutation permits recruitment of XPG and XPA. In marked contrast, in all the XP-B cells recruitment of XPF was absent immediately after UV and was delayed by 0.5 and 3h in cells from the mild and severely affected XP patients, respectively. Redistribution of NER proteins was nearly complete in normal cells by 3h but by 24h redistribution was only partially present in cells from mild patients and virtually absent in cells from the severely affected patients. Ineffectual repair of UV-induced photoproducts resulting from delayed recruitment and impaired redistribution of NER proteins may contribute to the markedly increased frequency of skin cancer in XP patients.

PMID: 17509950 [PubMed - as supplied by publisher]





175084094: Cancer. 2007 May 16; [Epub ahead of print]

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Reduced XPC messenger RNA level may predict a poor outcome of patients with nonsmall cell lung cancer.

Wu YH, Cheng YW, Chang JT, Wu TC, Chen CY, Lee H.

Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, Republic of China.

BACKGROUND.: Homologous deletion of the xeroderma pigmentosum complementary group C (XPC) repair gene frequently causes lung adenocarcinoma in mice, suggesting that an XPC defect may play a critical role in lung tumorigenesis. The current study attempted to determine whether reduced XPC mRNA levels predict the clinical outcome of lung cancer patients. METHODS.: XPC, p27(kip) (cdk inhibitory protein), and S-phase kinase-associated protein (skp2) levels were evaluated by Western blot analysis in a series of lung cancer cell lines with different invasive abilities. Migration and invasive abilities were measured using a modified Boyden chamber without and with Matrigel, respectively. To test whether XPC affects cell invasive ability, XPC gene protein expression was reduced in low invasive cells by RNA interference (RNAi) and assayed with Boyden chamber. XPC mRNA levels in 126 nonsmall cell lung cancers (NSCLCs) were examined by real-time-reverse-transcriptase polymerase chain reaction (RT-PCR). The prognostic value of XPC mRNA expression was statistically analyzed by the Kaplan-Meier method and Cox proportional hazards regression. RESULTS.: The expression of XPC was reduced with increasing invasive potential in CL1-series lung cancer cell lines. When the XPC level was reduced by RNAi, cell migration and invasiveness increased markedly; the increased invasiveness may be caused by decreased expression of p27(kip) and increased expression of skp2 and E2F transcription factor 1. To determine whether reduced XPC expression was correlated with tumor aggressiveness and poor patient survival, XPC mRNA levels were evaluated by real-time RT-PCR. Kaplan-Meier analysis demonstrated that the median survival of patients with lower XPC mRNA levels was shorter compared with patients with higher XPC mRNA levels (P = .0440). Cox regression analysis further indicated that XPC mRNA level may act as an independent prognostic factor for NSCLC patients (P = .014). CONCLUSIONS.: The results of the current study suggest that reduced XPC mRNA level may constitute an independent prognostic factor for NSCLC patients. Cancer 2007. (c) 2007 American Cancer Society.

PMID: 17508409 [PubMed - as supplied by publisher]





174983155: BMC Cancer. 2007 May 13;7(1):81 [Epub ahead of print]

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Sequence variations in DNA repair gene XPC is associated with lung cancer risk in a Chinese population: a case-control study.

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

ABSTRACT: BACKGROUND: The nucleotide excision repair (NER) protein, xeroderma pigmentosum C (XPC), participates in recognizing DNA lesions and initiating DNA repair in response to DNA damage. Because mutations in XPC cause a high risk of cancer in XP patients, we hypothesized that inherited sequence variations in XPC may alter DNA repair and thus susceptibility to cancer. METHODS: In this hospital-based case-control study, we investigated five XPC tagging, common single nucleotide polymorphisms (tagging SNPs) in 1,010 patients with newly diagnosed lung cancer and 1,011 matched cancer free controls in a Chinese population. RESULTS: In individual tagging SNP analysis, we found that rs3731055AG+AA variant genotypes were associated with a significantly decreased risk of lung adenocarcinoma [adjusted odds ratio (OR), 0.71; 95% confidence interval (CI), 0.56 - 0.90] but an increased risk of small cell carcinomas [adjusted OR, 1.79; 95% CI, 1.05 - 3.07]. Furthermore, we found that haplotype ACCCA was associated with a decreased risk of lung adenocarcinoma [OR, 0.78; 95% CI, 0.62 - 0.97] but an increased risk of small cell carcinomas [OR, 1.68; 95% CI, 1.04 - 2.71], which reflected the presence of rs3731055A allele in this haplotype. Further stratified analysis revealed that the protective effect of rs3731055AG+AA on risk of lung adenocarcinoma was more evident among young subjects and never smokers. CONCLUSION: These results suggest that inherited sequence variations in XPC may modulate risk of lung cancer, especially lung adenocarcinoma, in Chinese populations. However, these findings need to be verified in larger confirmatory studies with more comprehensively selected tagging SNPs.

PMID: 17498315 [PubMed - as supplied by publisher]






[Effect of estrogen on nucleotide excision repair of N2a neroblastoma cells]

[Article in Japanese]

Yoshioka A, Yamamoto A, Mori T, Nakamura Y, Morikawa M, Yoshino H, Kiuchi K, Makinodan M, Kishimoto T.

Department of Psychiatry,,

Until now reduced estrogen level has been considered to affect some psychiatric symptoms, because there are sex differences in onset of Schizophrenia and Alzheimer's disease. Estrogen is associated with cognitive functions, and it has been reported to protect oxidative damage of DNA related to base excision repair (BER). Some patients with Xeroderma Pigmentosum, who have normal BER and impaired nucleotide excision repair (NER), are known to be suffering from mental retardation. Therefore we hypothesized that impaired NER was partly associated with pathology of mental disorder and investigated the effects of estrogen on NER for ultraviolet-induced DNA damage. The N2a neuroblastoma cell line was used as a representative of neuronal cells and 17p-estradiol was selected as one of the most active estrogen derivatives. There were no significant effects of 17p-estradiol on prevention of DNA damage, promotion of DNA repair, or cell survival at the concentration of 0-0.1 microM 17p-estradiol (below cytotoxicity level). These results described that estrogen might not directly affect NER except through another DNA repair system.

Publication Types:

English Abstract


PMID: 17515114 [PubMed - in process]





175129212: Chem Biol Interact. 2007 Apr 19; [Epub ahead of print]

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Preferential binding of human XPA to the mitomycin C-DNA interstrand crosslink and modulation by arsenic and cadmium.

Mustra DJ, Warren AJ, Wilcox DE, Hamilton JW.

Department of Pharmacology & Toxicology, Dartmouth Medical School, Hanover, NH 03755-3835, United States; Center for Environmental Health Sciences, Dartmouth Medical School, Hanover, NH 03755-3851, United States.

The Xeroderma Pigmentosum A (XPA) protein is involved in the DNA damage recognition and repair complex formation steps of nucleotide excision repair (NER), and has been shown to preferentially bind to various forms of DNA damage including bulky lesions. DNA interstrand crosslinks are of particular interest as a form of DNA damage, since these lesions involve both strands of duplex DNA and present special challenges to the repair machinery, and mitomycin C (MMC) is one of several useful cancer chemotherapy drugs that induce these lesions. Purified XPA and the minimal DNA-binding domain of XPA are both fully capable of preferentially binding to MMC-DNA interstrand crosslinks in the absence of other proteins from the NER complex. Circular dichroism (CD) and gel shift assays were used to investigate XPA-DNA binding and to assess changes in secondary structure induced as a consequence of the interaction of XPA with model MMC-crosslinked and unmodified DNAs. These studies revealed that while XPA demonstrates only a modest increase in affinity for adducted DNA, it adopts a different conformation when bound to MMC-damaged DNA than when bound to undamaged DNA. This change in conformation may be more important in recruiting other proteins into a competent NER complex at damaged sites than preferential binding per se. Arsenic had little effect on XPA binding even at toxic concentrations, whereas cadmium reduced XPA binding to DNA to 10-15% that of Zn-XPA, and zinc addition could only partially restore activity. In addition, there was little or no change in conformation when Cd-XPA bound MMC-crosslinked DNA even though it demonstrated preferential binding, which may contribute to the mechanism by which cadmium can act as a co-mutagen and co-carcinogen.

PMID: 17512921 [PubMed - as supplied by publisher]





172595433: Eukaryot Cell. 2007 Apr;6(4):641-9. Epub 2007 Jan 26.

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Spliced leader RNA gene transcription in Trypanosoma brucei requires transcription factor TFIIH.

Lee JH, Nguyen TN, Schimanski B, Gunzl A.

Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3301, USA.

Trypanosomatid parasites share a gene expression mode which differs greatly from that of their human and insect hosts. In these unicellular eukaryotes, protein-coding genes are transcribed polycistronically and individual mRNAs are processed from precursors by spliced leader (SL) trans splicing and polyadenylation. In trans splicing, the SL RNA is consumed through a transfer of its 5'-terminal part to the 5' end of mRNAs. Since all mRNAs are trans spliced, the parasites depend on strong and continuous SL RNA synthesis mediated by RNA polymerase II. As essential factors for SL RNA gene transcription in Trypanosoma brucei, the general transcription factor (GTF) IIB and a complex, consisting of the TATA-binding protein-related protein 4, the small nuclear RNA-activating protein complex, and TFIIA, were recently identified. Although T. brucei TFIIA and TFIIB are extremely divergent to their counterparts in other eukaryotes, their characterization suggested that trypanosomatids do form a class II transcription preinitiation complex at the SL RNA gene promoter and harbor orthologues of other known GTFs. TFIIH is a GTF which functions in transcription initiation, DNA repair, and cell cycle control. Here, we investigated whether a T. brucei TFIIH is important for SL RNA gene transcription and found that silencing the expression of the highly conserved TFIIH subunit XPD in T. brucei affected SL RNA gene synthesis in vivo, and depletion of this protein from extract abolished SL RNA gene transcription in vitro. Since we also identified orthologues of the TFIIH subunits XPB, p52/TFB2, and p44/SSL1 copurifying with TbXPD, we concluded that the parasite harbors a TFIIH which is indispensable for SL RNA gene transcription.

Publication Types:

Research Support, N.I.H., Extramural

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



PMID: 17259543 [PubMed - indexed for MEDLINE]






168896961: Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2006 Jul;24(7):390-3.

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[Association between polymorphisms of XPD gene and susceptibility to chronic benzene poisoning]

[Article in Chinese]

Huang HL, Xu JN, Wang QK, Wang YW, Yang M, Chen Y, Li GL.

Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China.

OBJECTIVE: To explore the relationship between genetic polymorphisms of XPD gene and susceptibility to chronic benzene poisoning. METHODS: A case control study was conducted. Eighty patients diagnosed with chronic benzene poisoning and 62 workers occupationally exposed to benzene who were engaged in the same working time and job title as patients were investigated. PCR-RFLP was used for detecting the single nucleotide polymorphisms (SNPs) on codon156, codon312 and codon751 of XPD gene. RESULTS: There was a 2.903 times (95% CI: 1.054 - 7.959, P = 0.039 2) increased risk of chronic benzene poisoning in the subjects carrying XPD 751Gln variant allele compared with those carrying XPD 751Lys/Lys genotype, after adjusted for sex, length of service, smoking and drinking status. CONCLUSION: The subjects with XPD 751Gln variant allele are more susceptive to benzene.

Publication Types:

English Abstract

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



PMID: 16889696 [PubMed - indexed for MEDLINE]