Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An encounter between a DNA-translocating enzyme and a DNA-bound protein must occur frequently in the cell, but little is known about its outcome. Here we developed a multicolor single-molecule fluorescence approach to simultaneously monitor single-stranded DNA (ssDNA) translocation by a helicase and the fate of another protein bound to the same DNA. Distance-dependent fluorescence quenching by the iron-sulfur cluster of the archaeal XPD (Rad3) helicase was used as a calibrated proximity signal. Despite the similar equilibrium DNA-binding properties, the two cognate ssDNA-binding proteins RPA1 and RPA2 differentially affected XPD translocation. RPA1 competed with XPD for ssDNA access. In contrast, RPA2 did not interfere with XPD-ssDNA binding but markedly slowed down XPD translocation. Mechanistic models of bypassing DNA-bound proteins by the Rad3 family helicases and their biological implications are discussed.
Mol Cell 2009 Sep 11
PMID:Single-molecule analysis reveals differential effect of ssDNA-binding proteins on DNA translocation by XPD helicase. 1974 51

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair and also associated with various systemic symptoms. Approximately half of TTD patients exhibit photosensitivity, resulting from the defect in the nucleotide excision repair. Photosensitive TTD is due to mutations in three genes encoding XPB, XPD and p8/TTDA subunits of the DNA repair/transcription factor TFIIH. Mutations in these subunits disturb either the catalytic and/or the regulatory activity of the two XPB, XPD helicase/ATPases and consequently are defective in both, DNA repair and transcription. Moreover, mutations in any of these three TFIIH subunits also disturb the overall architecture of the TFIIH complex and its ability to transactivate certain nuclear receptor-responsive genes, explaining in part, some of the TTD phenotypes.
Hum Mol Genet 2009 Oct 15
PMID:Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH. 1980

For mammalian nucleotide excision repair (NER), DNA lesions are recognized in at least two steps involving detection of unpaired bases by the XPC protein complex and the subsequent verification of injured bases. Although lesion verification is important to ensure high damage discrimination and the accuracy of the repair system, it has been unclear how this is accomplished. Here, we show that damage verification involves scanning of a DNA strand from the site where XPC is initially bound. Translocation by the NER machinery exhibits a 5'-to-3' directionality, strongly suggesting involvement of the XPD helicase, a component of TFIIH. Furthermore, the initial orientation of XPC binding is crucial in that only one DNA strand is selected to search for the presence of lesions. Our results dissect the intricate molecular mechanism of NER and provide insights into a strategy for mammalian cells to survey large genomes to detect DNA damage.
Mol Cell 2009 Nov 25
PMID:Two-step recognition of DNA damage for mammalian nucleotide excision repair: Directional binding of the XPC complex and DNA strand scanning. 1994 24

Homologous recombination is a major double-strand break (DSB) repair mechanism that acts during the S and G2 phases. In contrast, nucleotide excision repair (NER) is a major pathway for the repair of DNA bulky adducts that is unrelated to replication. We show that replication can be strongly disturbed in a specific type of rad3/XPD NER mutant of TFIIH, causing replication fork breakage. In contrast to classical NER-deficient mutations, the S. cerevisiae rad3-102 allele, which has a minimal impact on UV resistance, channels bulky adducts into DSBs. rad3-102 allows Rad1/XPF- and Rad2/XPG-catalyzed DNA incisions but fails to perform postincision steps retaining TFIIH at the damaged site. Broken forks are rescued by MRX-Rad52-Rfc1-dependent recombination via two types of replication restart mechanisms, one being Rad51 dependent and the other Pol32 dependent. Our results define the genetic and molecular hallmarks of replication fork breakage and restart and bring insights to understand specific NER-related human syndromes.
Mol Cell 2010 Mar 12
PMID:A postincision-deficient TFIIH causes replication fork breakage and uncovers alternative Rad51- or Pol32-mediated restart mechanisms. 2022 72

Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of gastric antrum adenocarcinoma (GAA) related to Helicobacter pylori infection. This study, including 361 GAAs and 616 controls without any evidence of tumors, was designed to evaluate the association between the polymorphisms of DNA repair genes XPC Ala499Val (RS#2228000) and Lys939Gln (RS#2228001), XPD Lys751Gln (RS#13181), and XRCC4 Ala247Ser (RS#3734091) and Ser298Asn (RS#1805377), and GAA risk for Guangxi population by means of TaqMan-PCR analysis. Increased risks of GAA were found for individuals with H. pylori positive [odds ratio (OR), 2.48; 95% confidence interval (CI), 1.84-3.33] or cagA positive (OR, 7.34; 95% CI, 5.46-9.87). No differences were observed among the studied groups with regard to the genotype distribution of XPC codons 499 and 939 and of XRCC4 codon 247; but XPD codon 751 genotypes with Gln [ORs (95% CI) were 2.67 (1.98-3.58) and 3.97 (2.64-5.99) for Lys/Gln and Gln/Gln, respectively] and XRCC4 codon 298 genotypes with Asn [ORs (95% CI) were 3.01 (2.21-4.10) and 4.78 (3.24-7.05) for Ser/Asn and Asn/Asn, respectively] increased the risk of GAA. Interestingly, there was an interactive effect between the risk genotypes of these two genes and cagA-positive status in the GAA risk (OR(interact) = 2.05 and 2.08, respectively). However, we did not find the gene-H. pylori-status interaction effects on the risk of GAA (P(interact) > 0.05). The results suggested that the polymorphisms of XPD codon 751 and XRCC4 codon 298 are associated with an increased risk of developing H. pylori-related GAA among Guangxi population.
Mol Carcinog 2010 Jun
PMID:Genetic polymorphisms in DNA repair genes XPC, XPD, and XRCC4, and susceptibility to Helicobacter pylori infection-related gastric antrum adenocarcinoma in Guangxi population, China. 2023 59

Several polymorphisms in the DNA repair gene are thought to have significant effects on cancer risk. We investigated the association of polymorphisms in the DNA repair genes XRCC1 Arg399Gln, XRCC3 Thr241Met, XPD Lys751Gln, XPG Asp1104His, APE1 Asp148Glu, and HOGG1 Ser326Cys with endometriosis risk. Genotypes were determined by PCR-RFLP assays in 52 patients with endometriosis and 101 age-matched healthy controls. Although there were no significant (P > 0.05) differences in the frequencies of genotypes or alleles of APE1, XRCC1, XPD, XPG, and HOGG1 genes between patients and controls, the frequency of the XRCC3 Thr/Thr genotype was significantly greater in endometriosis patients compared with controls (P = 0.005). XRCC3 Thr/Met genotypes (P = 0.022), and the Met allele (P = 0.005) seem to have a protective role against endometriosis. The distributions of genotypes and alleles of the genes APE1, XRCC1, XRCC3, XPD, XPG, and HOGG1 were not significantly associated with the different stages of endometriosis (P > 0.05). We conclude that the XRCC3 Thr/Thr genotype is associated with endometriosis in Turkish women.
Genet Mol Res 2010 Apr 06
PMID:DNA repair genes in endometriosis. 2039 47

In the present study we investigated the association between three polymorphisms of the MUTYH (Tyr165Cys, rs34612342), the OGG1 (Ser326Cys, rs1052133) and the XPD (Lys751Gln, rs13181) genes with head and neck cancer risk. Genotypes were determined in DNA from peripheral blood lymphocytes of 265 patients with head and neck squamous cell carcinoma (HNSCC) as well as 280 cancer-free controls by PCR-restriction fragment length polymorphisms. We found an association between HNSCC and the Ser326Cys (OR 1.69; 95% CI 1.19-2.45) as well as Cys326Cys (OR 4.56; 95% CI 2.07-10.05) variants of the OGG1 gene. The gene-gene interaction between MUTYH and OGG1 as well as OGG1 and XPD polymorphic variants may contribute to higher prevalence of HNSCC. We also found an association between Ser326Cys and Cys326Cys variants of OGG1 gene and smoking status in HNSCC patients (OR 1.97; 95% CI 1.25-3.11), (OR 3.54; 95% CI 1.39-9.04), respectively. Moreover, we also observed a protective association between Tyr165Cys variant of the MUTYH gene and non-smoking status in HNSCC (OR 0.34; 95% CI 0.17-0.66). We also found a link between gene-gene interaction (MUTYH and OGG1 or OGG1 and XPD) and smoking (ORs 2.17-4.20 and 2.18-5.23) or non-smoking status (ORs 0.11 and 7.61) in HNSCC patients, respectively. In conclusion our data showed that the Ser326Cys polymorphism of the OGG1 gene may modify the risk of HNSCC associated with smoking. Finally we suggested that this polymorphism might be used as predictive factor for head and neck cancer in Polish population.
Mol Biol Rep 2011 Feb
PMID:MUTYH Tyr165Cys, OGG1 Ser326Cys and XPD Lys751Gln polymorphisms and head neck cancer susceptibility: a case control study. 2057 8

The contribution of polymorphisms of DNA repair genes OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln in developing colorectal carcinoma is controversial. Whether the group 1A carcinogen Helicobacter pylori is a risk factor or not in these patients could not be clearly elucidated. One hundred ten colorectal cancer patients and 116 cancer-free individuals constituted the test and control groups, respectively. The association of OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln polymorphisms and the susceptibility to colorectal carcinoma with or without oxidative stress were evaluated. DNA was extracted from peripheral blood cells and genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. For serum nitric oxide and total antioxidant status assay, spectrophotometric analyses were used. Serum albumin measurements were performed using an autoanalyzer. H. pylori IgG was measured by ELISA. The serum albumin concentrations of cancer patients were significantly lower than those of the controls (p < 0.05). The carriers of the variant genotype of OGG1 (odds ratio: 0.963; 95% confidence interval: 0.446-2.079), XPC (0.789, 0.366-1.700), or XPD (0.532, 0.259-1.094) did not associate with the increased risk of cancer progression, despite the increased oxidative stress in cancer patients. Seropositivity of H. pylori IgG has been found to increase the risk of colorectal carcinoma by 2.2-fold.
Genet Test Mol Biomarkers 2010 Aug
PMID:Oxidative stress, Helicobacter pylori, and OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln polymorphisms in a Turkish population with colorectal carcinoma. 2064 33

Xeroderma pigmentosum group D (XPD) protein is one of the subunits of TFIIH that is required for nucleotide excision repair and transcription. We found a XPD protein complex containing MMS19 that was assumed to be a regulator of TFIIH. However, the MMS19-XPD complex did not contain any other subunits of TFIIH. Instead, it included FAM96B (now designated MIP18), Ciao1, and ANT2. MMS19, MIP18, and XPD localized to the mitotic spindle during mitosis. The siRNA-mediated knockdown of MMS19, MIP18, or XPD led to improper chromosome segregation and the accumulation of nuclei with abnormal shapes. In addition, the frequency of abnormal mitosis and nuclei was increased in XP-D and XP-D/CS patients' cells. These results indicate that the MMS19-XPD protein complex, now designated MMXD (MMS19-MIP18-XPD), is required for proper chromosome segregation, an abnormality of which could contribute to the pathogenesis in some cases of XP-D and XP-D/CS.
Mol Cell 2010 Aug 27
PMID:MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in chromosome segregation. 2079 33

DNA repair genetic polymorphisms have been studied extensively in relation to lung cancer susceptibility, but much less is known about their role in clinical outcome modulation. In this report, we examined effect of the XPA -4G>A, XPD Asp312Asn, Leu751Gln, hHR23B Ala249Val, XPG Asp1104His, XRCC1 Arg399Gln, XRCC2 -4234G>C and XRCC3 Thr241Met polymorphisms on overall survival in 162 patients with resected non-small cell lung cancer (NSCLC). The XRCC3 Met/Met genotype was significantly associated with increased risk of death among all patients and men in uni- and multivariate analyses. The risk was higher for adenocarcinoma patients possessing the XRCC3 Met/Met or XRCC1 Gln/Gln genotypes, although their frequency was small. The XRCC1 399Gln allele was also associated with poor prognosis in stage II-IIIA and among older individuals. Men homozygous for the XPD 312 Asn/Asn had significantly better survival with the risk of death being at borderline significance in uni- and multivariate models. Younger cases and ever smokers smoking less than median pack-years showed significantly increased risk of death associated with the XPA -4A allele. A presence of one or two XRCC2 -4234C alleles had a protective effect in males and ever smokers with lower cumulative smoking dose, although the CC genotype was rarely observed. When number of combined risk alleles was considered, we found that carriers of >4 adverse alleles were at significantly increased risk of death in uni- and multivariate models. Therefore, our results indicate that selected genetic polymorphisms in DNA repair genes may influence overall survival in resected NSCLC.
Mol Biol Rep 2011 Nov
PMID:An association between DNA repair gene polymorphisms and survival in patients with resected non-small cell lung cancer. 2118 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>