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[Correlation of genetic polymorphisms in nucleotide excision repair system to sensitivity of advanced non-small cell lung cancer patients to platinum-based chemotherapy].

BACKGROUND & OBJECTIVE: DNA repair system plays an important role in tumor sensitivity to platinum-based chemotherapy. This study was to examine the correlations of polymorphisms in nucleotide excision repair system to sensitivity of advanced non-small cell lung cancer (NSCLC) to platinum-based chemotherapy. METHODS: Treatment outcomes of 200 advanced NSCLC patients, treated with platinum-based chemotherapy, were evaluated. XPC-PAT, XPD Lys751Gln (rs1052559), and ERCC1 C8092A (rs1052559) were genotyped by polymerase chain reaction-amplified fragment length polymorphism (PCR-AFLP) or PCR-restr

Influence of DNA repair gene polymorphisms on the yield of chromosomal aberrations.

We evaluated the influence of several DNA repair gene polymorphisms on the frequency of chromosomal aberrations (CAs) analyzed in peripheral lymphocytes, using the fluorescence in situ hybridization technique. The CA data were obtained from an earlier study of 84 healthy nonsmokers (48 women and 36 men) carefully characterized for indoor radon exposure. The frequency of translocations showed a wide interindividual variability, which was only partly explained by age. To investigate the potential role of DNA repair polymorphisms in this variation, genotypes of DNA repair genes OGG1 (codon 326),

XPD gene polymorphism and host characteristics in the association with cutaneous malignant melanoma risk.

We recently reported an association between low DNA repair capacity, measured through the host-cell reactivation assay, and melanoma risk in subjects with dysplastic naevi or low tanning ability. We investigated the genetic basis for these findings by analysing the Asp312Asn and Lys751Gln polymorphisms of the XPD (ERCC2) DNA repair gene in the same subjects. Similar to our previous report, no significant association between XPD polymorphisms and melanoma risk was found in 176 melanoma cases and 177 controls (odds ratio (OR)=1.5, 95% confidence interval (CI)=0.9-2.5 for 312Asn; OR=1.3, 95% CI=0

Quiescent murine cells lack global genomic repair but are proficient in transcription-coupled repair.

The majority of the cells in the body, including stem cells, exist in a quiescent state, so it is in quiescent cells where most DNA damage occurs. It has been uncertain whether or not this damage is repaired or fixed into mutations during quiescence or if proliferation is required for both. Prior to the development of transgenic mice, it was difficult to distinguish between these two possibilities, as cells had to proliferate to form colonies before mutations could be detected. Transgenes, however, can be shuttled out of quiescent mouse cells directly, and the level of DNA damage and mutation

DNA damage and mutations induced by arachidonic acid peroxidation.

Endogenous cellular oxidation of omega6-polyunsaturated fatty acids (PUFAs) has long been recognized as a contributing factor in the development of various cancers. The accrual of DNA damage as a result of reaction with free radical and electrophilic aldehyde products of lipid peroxidation is believed to be involved; however, the genotoxic and mutation-inducing potential of specific membrane PUFAs remains poorly defined. In the present study we have examined the ability of peroxidizing arachidonic acid (AA, 20:4omega6) to induce DNA strand breaks, base modifications, and mutations. The time-de

Molecular anatomy of the human excision nuclease assembled at sites of DNA damage.

Human nucleotide excision repair is initiated by six repair factors (XPA, RPA, XPC-HR23B, TFIIH, XPF-ERCC1, and XPG) which sequentially assemble at sites of DNA damage and effect excision of damage-containing oligonucleotides. We here describe the molecular anatomy of the human excision nuclease assembled at the site of a psoralen-adducted thymine. Three polypeptides, primarily positioned 5' to the damage, are in close physical proximity to the psoralen lesion and thus are cross-linked to the damaged DNA: these proteins are RPA70, RPA32, and the XPD subunit of TFIIH. While both XPA and XPC bin

XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects.

DNA repair genes have an important role in protecting individuals from cancer-causing agents. Polymorphisms in several DNA repair genes have been identified and individuals with non-dramatic reductions in the capacity to repair DNA damage are observed in the population, but the impact of specific genetic variants on repair phenotype and cancer risk has not yet been clarified. In 308 healthy Italian individuals belonging to the prospective European project EPIC, we have investigated the relationship between DNA damage, as measured by (32)P-DNA adduct levels, and three genetic polymorphisms in d

DNA damage in the nucleosome core is refractory to repair by human excision nuclease.

To investigate the effect of nucleosomes on nucleotide excision repair in humans, we prepared a mononucleosome containing a (6-4) photoproduct in the nucleosome core and examined its repair with the reconstituted human excision nuclease system and with cell extracts. Nucleosomal DNA is repaired at a rate of about 10% of that for naked DNA in both systems. These results are in agreement with in vivo data showing a considerably slower rate of repair of overall genomic DNA relative to that for transcriptionally active DNA. Furthermore, our results indicate that the first-order packing of DNA in n

XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case-control analysis.

DNA repair capacity is central in maintaining normal cellular functions. Variants of several DNA repair genes,including the nucleotide excision repair gene XPD, have been described recently. Because we previously reported that patients with squamous cell carcinoma of the head and neck (SCCHN) had lower DNA repair capacity than healthy controls, we hypothesized that inherited polymorphisms of XPD may contribute to genetic susceptibility to SCCHN, a tobacco-related cancer. To test this hypothesis, we conducted a hospital-based case-control study of 189 SCCHN patients and 496 cancer-free controls

Site-specific rates of excision repair of benzo[a]pyrene diol epoxide adducts in the hypoxanthine phosphoribosyltransferase gene of human fibroblasts: correlation with mutation spectra.

When populations of repair-proficient diploid human fibroblasts were treated with (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) during early S phase, just as the hypoxanthine phosphoribosyltransferase gene (HPRT) was being replicated, 5% of the induced base substitutions were found at nt 212, and 5% of the substitutions were found at nt 229 in exon 3. However, when the population was treated in early G1 phase to allow at least 12 hr for repair before the onset of S phase, 21% of the substitutions were found at nt 212, and 10% were found at nt

Oncogenes and radiation carcinogenesis.

Current research indicates a role for several oncogenes in radiation-induced carcinogenesis in vivo and cell transformation in vitro. Certain oncogenes are probably also involved in some cases of human cancer caused by exposure to nonionizing radiation and may play a mechanistic role in the phenomenon of radioresistance seen in later stages of tumor progression. The mechanisms of oncogene activation seen in radiation-induced tumors include point mutations, gene amplification, and changes in gene expression. Genetic factors associated with target species, strain, and tissue type play an importa

Targeting the AMP-Activated Protein Kinase for Cancer Prevention and Therapy.

Despite the advances in biomedical research and clinical applications, cancer remains a leading cause of death worldwide. Given the limitations of conventional chemotherapeutics, including serious toxicities and reduced quality of life for patients, the development of safe and efficacious alternatives with known mechanism of action is much needed. Prevention of cancer through dietary intervention may hold promise and has been investigated extensively in the recent years. AMP-activated protein kinase (AMPK) is an energy sensor that plays a key role in the regulation of protein and lipid metabol

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… AMPK is required for the expression of xeroderma pigmentosum C (XPC) to promote DNA repair following UV damage ( 43 ). Figure 1 Function and regulation of AMPK leading to tumor suppression . … AMPK is necessary for the expression of xeroderma pigmentosum C (XPC) to promote DNA repair following UV damage. …

Association of XRCC1 (rs1799782) and XPD (rs13181) gene polymorphisms with renal failure risk in a sample of Iraqi population: a case-control study.

BACKGROUND: End-stage chronic kidney disease (CKD) can lead to life-threatening complications and is caused primarily by CKD and cardiovascular issues. CKD is characterized by the inability of the kidneys to filter waste and excess fluids from the blood. This study investigated the associations of the genetic variants XRCC1 rs1799782 (C194T) and ERCC2/XPD rs25487 (Q399R) with CKD susceptibility in Iraqi patients and related biochemical changes. METHODS: The research was performed from 25/01/2023 to 30/06/2023, we analyzed the genetic associations of two SNPs of DNA repair genes (XRCC1 and ERC

Predictive Value of ERCC1, ERCC2, and XRCC Expression for Patients with Locally Advanced or Metastatic Gastric Cancer Treated with Neoadjuvant mFOLFOX-4 Chemotherapy.

The dismal outcome in patients with locally advanced or metastatic gastric cancer (GC) highlights the need for effective systemic neoadjuvant chemotherapy to improve clinical results. This study evaluated the correlation between the expression of three DNA repair genes, namely the excision repair cross-complementing group 1 (ERCC1), excision repair cross-complementing group 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1) and the clinical outcome of patients with locally advanced or metastatic GC treated with mFOLFOX-4 neoadjuvant chemotherapy. Fifty-eight patients with histol

ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer.

PURPOSE: DNA-damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC. EXPERIMENTAL DESIGN: Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however,

DNA Repair Gene (XPD, XRCC4, and XRCC1) Polymorphisms in Patients with Endometrial Hyperplasia: A Pilot Study.

BACKGROUND In this study, we aimed to evaluate the association between endometrial hyperplasia and DNA repair gene (XPD, XRCC4, and XRCC1) polymorphisms. MATERIAL AND METHODS There were 114 cases enrolled in the study in 4 groups: simple endometrial hyperplasia (SH) (Group 1), complex endometrial hyperplasia without atypia (CH) (Group 2), complex atypical endometrial hyperplasia (CAH) (Group 3), and normal endometrium (NE) (Group 4). Of these cases, 37 cases had SH, 36 cases had CH, 16 cases had CAH, and 25 cases had NE. To evaluate an association between atypia and DNA repair genes, we consid

Downregulated XPA promotes carcinogenesis of bladder cancer via impairment of DNA repair.

Bladder cancer is the most common malignant tumor of urinary system, largely resulting from failure of repair of DNA damage to the environmental insults. The function of XPA in nucleotide excision repair pathway has been well documented. However, participation of XPA in the repair of DNA double-strand break remains unknown. Here, we reported that bladder cancer expressed low XPA levels compared to adjacent non-tumor bladder tissue, and this phenotype was closely associated with chromosomal aberrations. Moreover, downregulated XPA appeared to increase incidence of chromosome aberration. XPA red

Association of XPD (Lys751Gln) and XRCC1 (Arg280His) gene polymorphisms in myelodysplastic syndrome.

Myelodysplastic syndromes (MDSs) are heterogeneous hematopoietic disease characterized by ineffective haematopoiesis that frequently transforms into acute leukaemia. Alterations in many individual biologic pathways have been reported in MDS pathophysiology. Disease progression along the MDS, acute myeloid leukemia (AML) continuum is believed to be a consequence of stepwise accumulation of DNA mutations which infers a defect in DNA repair. The present study investigated the association between DNA repair genes (XRCC1, XRCC3, OGG1, XPD and RAD51) and the risk of developing MDS. The study was car

DNA repair genes polymorphisms and risk of colorectal cancer in Saudi patients.

BACKGROUND AND STUDY AIMS: Polymorphisms in the DNA repair genes may influence individual capacity to repair DNA damage, which may be associated with increased genetic instability and carcinogenesis. Our aim was to evaluate the relation of genetic polymorphisms in 2 DNA repair genes, XPD Lys751Gln and XRCC1 (A399G), with colorectal cancer (CRC) susceptibility. We further investigated the potential effect of these DNA repair variants on clinicopathological parameters of CRC patients. PATIENTS AND METHODS: Both XPD and XRCC1 polymorphisms were characterised in one hundred CRC patients and one h