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Influence of DNA repair gene polymorphisms on the initial repair of MMS-induced DNA damage in human lymphocytes as measured by the alkaline comet assay.

We have applied the alkaline comet assay to study the functional impact of gene polymorphisms in base excision repair (APEX1 Asp148Glu, XRCC1 Arg194Trp, XRCC1 Arg399Gln) and homologous recombination repair (XRCC3 Thr241Met, NBS1 Glu185Gln), two pathways that play crucial roles in the repair of DNA damage induced by methylmethane sulphonate (MMS). We also examined the effect of polymorphisms in mismatch repair (MLH1 -93 A/G) and nucleotide excision repair (XPD Lys751Gln) as putative negative controls based on the limited roles of these pathways in MMS-induced repair. Phytohemagglutinin-stimulat

Stratification for smoking in case-cohort studies of genetic polymorphisms and lung cancer.

The risk estimates obtained in studies of genetic polymorphisms and lung cancer differ markedly between studies, which might be due to chance or differences in study design, in particular the stratification/match of comparison group. The effect of different strategies for stratification and adjustment for smoking on the estimated effect of polymorphisms on lung cancer risk was explored in the case-cohort design. We used an empirical and a statistical simulation approach. The stratification strategies were: no smoking stratification, stratification for smoking status and stratification for smok

Path analysis of biomarkers of exposure and early biological effects among coke-oven workers exposed to polycyclic aromatic hydrocarbons.

Many host factors or biomarkers are involved in the process of early DNA damage induced by occupational exposure to polycyclic aromatic hydrocarbons (PAH) as seen in coke-oven workers. This paper aimed to identify complicated causal interrelationship of various biomarkers using the path analysis. In this analysis, we included 235 subjects (166 coke-oven workers and 69 nonexposed controls) whose data on the comet assay (e.g., Olive tail moment) and cytogenetic analysis of peripheral blood lymphocytes as well as urinary 1-hydroxypyrene (1-OHP) were available. The path analysis showed that coke-o

Development of new EBV-based vectors for stable expression of small interfering RNA to mimick human syndromes: application to NER gene silencing.

We developed and characterized replicative small interfering RNA (siRNA) vectors for efficient, specific, and long-term gene silencing in human cells. We created stable XPA(KD) and XPC(KD) (knockdown) syngeneic cell lines to mimic human cancer-prone syndromes. We also silenced (HSA)KIN17. Several clones displaying undetectable protein levels of XPA, XPC, or (HSA)kin17 were grown for more than 300 days. This stability of gene silencing over several months of culture allows us to assess the specific involvement of these proteins in UVC sensitivity in syngeneic cells. Unlike XPA, (HSA)KIN17, and

XRCC1 and XPD genetic polymorphisms, smoking and breast cancer risk in a Finnish case-control study.

INTRODUCTION: It has been suggested that individuals with reduced DNA repair capacities might have increased susceptibility to environmentally induced cancer. In this study, we evaluated if polymorphisms in DNA repair genes XRCC1 (Arg280His, Arg399Gln) and XPD (Lys751Gln) modify individual breast cancer risk, with emphasis on tobacco smoking. METHODS: The study population consisted of 483 incident breast cancer cases and 482 population controls of Finnish Caucasian origin. The genotypes were determined by PCR-RFLP-based methods. Odds ratio (OR) and confidence intervals (CIs) were calculated b

[Study on the expression of DNA excision repair biomarkers in cispatin-treated lung cancer cell line].

OBJECTIVE: To study the expression levels of ERCC2, UDG, and PCNA in cisplatin-treated A549 cell line. METHOD: Comet assay, RT-PCR, and western blot were used to study the mRNA and protein expression levels of ERCC2, UDG, and PCNA. RESULTS: When treated with IC(20) cisplatin, the DNA damage level increased as the cisplatin treated time increased within 24 h of cisplatin treatment. The tail state 12 h and 24 h after treatment was 5.02 +/- 0.68 and 7.22 +/- 0.53 respectively, which was significantly higher than those of the controls (2.73 +/- 0.29). The tail state 24 h after treatment was not

XPD/ERCC2 EXON 8 Polymorphisms: rarity and lack of significance in risk of squamous cell carcinoma of the head and neck.

BACKGROUND: Inherited polymorphisms of DNA repair genes may contribute to genetic susceptibility to squamous cell carcinoma of the head and neck (SCCHN). The objective was to assess whether two polymorphisms in the nucleotide excision repair gene XPD (ERCC2) are markers of SCCHN risk. METHODS: We performed a hospital-based case-control study of 180 SCCHN patients and 400 cancer-free controls frequency matched on age, sex, smoking, and alcohol use. All subjects were non-Hispanic whites. XPD alleles 23047 and 23051 were assessed by digestion with the restriction enzymes XhoII and SphI after PCR

Early p53-positive foci as indicators of tumor risk in ultraviolet-exposed hairless mice: kinetics of induction, effects of DNA repair deficiency, and p53 heterozygosity.

p53 mutations appear to be early events in skin carcinogenesis induced by chronic UVB irradiation. Clusters of epidermal cells that express p53 in mutant conformation ("p53 positive foci") are easily detected by immunohistochemical staining long before the appearance of skin carcinomas or their precursor lesions. In a hairless mouse model, we determined the dose-time dependency of the induction of these p53+ foci and investigated the relationship with the induction of skin carcinomas. The density of p53+ foci may be a good direct indicator of tumor risk. Hairless SKH1 mice were exposed to eith

Transcription-coupled and global genome repair differentially influence UV-B-induced acute skin effects and systemic immunosuppression.

Exposure to UV-B radiation impairs immune responses in mammals by inhibiting especially Th1-mediated contact hypersensitivity and delayed-type hypersensitivity. Immunomodulation is not restricted to the exposed skin, but is also observed at distant sites, indicating the existence of mediating factors such as products from exposed skin cells or photoactivated factors present in the superficial layers. DNA damage appears to play a key role, because enhanced nucleotide excision repair (NER) strongly counteracts immunosuppression. To determine the effects of the type and genomic location of UV-ind

Resistance of human nucleotide excision repair synthesis in vitro to p21Cdn1.

The p21Cdn1 protein (cip1/waf1/sdi1) plays an important role as an inhibitor of mammalian cell proliferation in response to DNA damage. By interacting with and inhibiting the function of cyclin-Cdk complexes, p21 can block entry into S phase. p21 can also directly inhibit replicative DNA synthesis by binding to the DNA polymerase sliding clamp factor PCNA. When cells are damaged and p21 is induced, DNA nucleotide excision repair (NER) continues, even though this pathway is PCNA-dependent. We investigated features of p21-resistant NER using human cell extracts. A direct end-labelling approach w

Functional interactions between p53 and the TFIIH complex are affected by tumour-associated mutations.

The p53 tumour suppressor is mutated in the majority of human tumours. p53's proposed role as the guardian of the genome is reflected in its multiple effects on transcription genome stability, cell growth and survival. We show that p53 interacts both physically and functionally with the TFIIH complex. There are multiple protein-protein contacts, involving two regions of p53 and three subunits of TFIIH, ERCC2 (XPD), ERCC3 (XPB) and p62. p53 and its C-terminus (amino acids 320-393) inhibit both of the TFIIH helicases and in vitro transcription in the absence of TFIIH. Transcription inhibition is

Reconstitution of mammalian excision repair activity with mutant cell-free extracts and XPAC and ERCC1 proteins expressed in Escherichia coli.

Nucleotide excision repair in humans involves the coordinated actions of 8-10 proteins. To understand the roles of each of these proteins in excision it is necessary to develop an in vitro excision repair system reconstituted entirely from purified proteins. Towards this goal we have expressed in E. coli two of the 8 genes known to be essential for the excision reaction. XPAC and ERCC1 were expressed as fusion proteins with the Escherichia coli maltose binding protein (MBP) and purified to > 80% homogeneity by affinity chromatography. The purified proteins either as fusions or after cleavage f

A review of hereditary malignant melanoma including biomarkers in familial atypical multiple mole melanoma syndrome.

This review provides a comprehensive coverage of hereditary malignant melanoma with emphasis upon its heterogeneity as well as newly developed biomarker investigations. The recently described familial atypical multiple mole melanoma (FAMMM) syndrome is featured. Particular attention has been given to findings of increased hyperdiploidy observed as an in vitro phenomenon in cultured skin fibroblasts from high-risk and FAMMM-affected subjects. The FAMMM genotype is complex in that it predisposes a patient not only to melanoma (cutaneous and intraocular malignant melanoma) but also to other histo

Design and implementation of an Internet-Based cancer risk assessment tool: Use over 10 years.

BackgroundPrevention and early intervention can improve survival and quality of life across all cancers. Patient understanding of risk factors and associated actionable lifestyle changes and screening programs is not well understood by clinicians METHODS: An Internet-based tool, Reduce My Risk, was created in 2009 and made available on oncolink.org. Users voluntarily completed a survey regarding demographics and cancer risk factors, and received information about their cancer risk RESULTS: Twenty eight thousand and one surveys were completed from 2009 to 2019. Median age was 26 years (18-101);

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… pigmentosum | No | 99% | 27,756 | | No | 100% | 27,956 | | Yes | 1% | 245 | | Yes | 0% | 45 | Have you ever been diagnosed with: Crohn's disease | Have you or a family member ever tested positive for/been told you have: BRCA1 | No | 99% | 27,820 | | No | 99% | 27,633 | | Yes | 1% | 181 | … In a similar vein, this survey captures individuals with uncommon personal medical histories, such as Fanconi anemia (54 surveys), xeroderma pigmentosum (45 surveys), primary sclerosing cholangitis (43 surveys), and others. …

Nucleotide excision repair of abasic DNA lesions.

Apurinic/apyrimidinic (AP) sites are a class of highly mutagenic and toxic DNA lesions arising in the genome from a number of exogenous and endogenous sources. Repair of AP lesions takes place predominantly by the base excision pathway (BER). However, among chemically heterogeneous AP lesions formed in DNA, some are resistant to the endonuclease APE1 and thus refractory to BER. Here, we employed two types of reporter constructs accommodating synthetic APE1-resistant AP lesions to investigate the auxiliary repair mechanisms in human cells. By combined analyses of recovery of the transcription r

Significant association between ERCC2 and MTHR polymorphisms and breast cancer susceptibility in Moroccan population: genotype and haplotype analysis in a case-control study.

BACKGROUND: Genetic determinants of breast cancer (BC) remained largely unknown in the majority of Moroccan patients. The purpose of this study was to explore the association of ERCC2 and MTHFR polymorphisms with genetic susceptibility to breast cancer in Moroccan population. METHODS: We genotyped ERCC2 polymorphisms (rs1799793 (G934A) and rs13181 (A2251C)) and MTHFR polymorphisms (rs1801133 (C677T) and rs1801131 (A1298C)) using TaqMan SNP Genotyping Assays. Genotypes were compared in 151 BC cases and 156 population-matched controls. Allelic, genotypic and haplotype associations with the risk

Breast cancer in an 18-year-old female: A fatal case report and literature review.

Breast cancer (BC) is the most frequent malignancy in both pre- and postmenopausal women. However, it is exceedingly rare in very young patients, and especially in adolescents. Herein, we report a case of an 18-year-old female diagnosed with invasive BC. The proband had been found to be negative for BC in close family members. A common BC genetic screening test for the Polish population did not detect any known founder mutations in the BRCA1 gene. Further evaluation identified a p.Ile157Thr (I157T) mutation in the CHEK2 gene, a p.Ala1991Val (A1991V) variant of unknown significance in the BRCA2