Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0043346 (xeroderma pigmentosum)
2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differential hybridization was used to detect repair defects in xeroderma pigmentosum (XP) that are not amenable to current analyses. cDNA libraries were constructed from cytoplasmic RNA of normal and XP fibroblast strains (complementation groups A and D) and analyzed for differential gene expression. More than 40,000 lambda gt10 cDNA clones were differentially screened with in vitro transcripts made from cDNA in the pBluescript vector. Six differential clones were detected in the libraries of the XP group A and D strains which caused stronger or weaker signals when probed with transcripts from XP strains than with those from the normal strains. Two clones coded for mitochondrial genes: mitochondrial 16 S rRNA and ATPase 6L. Overexpression of mitochondrial genes in XP may indicate that functions of the ATP-generating system are impaired since such functions are intensified whenever they become insufficient, for example as a consequence of DNA damage. It is tempting to assume that abnormal mitochondria are one of the causes for the neurological malfunctions in XP. Furthermore, densitometric analysis of Northern blots revealed that mRNA of lactate dehydrogenase, chain M, was less abundant in four XP group A strains (extent of reduction: 70%) and in two XP group D strains (extent of reduction: 58%). Enzyme activity was also diminished. In addition, mRNA of the gene for glyceraldehyde-3-phosphate dehydrogenase was less expressed in the same XP group A and D fibroblast strains investigated (reduction in both complementation groups: 50%). Both glycolytic enzymes have nuclear functions apart from their role in sugar metabolism. Lactate dehydrogenase, chain M, is identical to a helix-destabilizing protein; it is closely associated with chromatin and unfolded DNA, suggesting a role in DNA synthesis and transcription. The 37-kDa subunit of glyceraldehyde-3-phosphate dehydrogenase is involved in transcription and was shown to be identical to uracil-DNA glycosylase, a base-excision repair enzyme. We presume that the nuclear functions of these glycolytic enzymes may be thwarted in the XP strains investigated and may account for malfunctions in XP, particularly for neurological disturbances.
...
PMID:Expression of mitochondrial genes and DNA-repair-related nuclear genes is altered in xeroderma pigmentosum fibroblasts. 820 43

cDNA libraries constructed from cytoplasmic RNA of normal and xeroderma pigmentosum (XP) fibroblast strains were screened for differential gene expression. XP fibroblast strains included one representative of the complementation groups A, C, D, and one XP variant strain. The XP lambda gt10 cDNA libraries were differentially screened with in vitro transcripts made from cDNA in the pBluescript vector using both the same XP strain and the normal fibroblast strain. Eight differential clones were detected in the libraries of the XP group A, D, and C strains, which caused stronger signals when probed with transcripts from XP strains than with those from the normal strain. The cDNA clones were sequenced. Seven of the eight clones detected coded for three mitochondrial genes: subunit I of cytochrome c oxidase (complex IV of the respiratory chain), apocytochrome b (subunit of complex III), and 16-S rRNA. Two clones representing essentially (a) subunit I of cytochrome c oxidase and (b) 16-S rRNA diverged from the sequence of the human mitochondrial genome present in the data-base libraries. Clone a exhibited a transition mutation, clone b reflected a transcript of a mitochondrial genome rearranged in the 16-S rRNA gene, including four nucleotides of the adjacent tRNA(Leu) gene. The apparently enhanced expression of mitochondrial genes in XP cells, together with the changes in DNA sequence, seem to indicate that functions of the ATP-generating system were impaired. This defect may have originated from mutations due to lack of DNA repair. The data can be interpreted in the light of mitochondrial changes that cause human neuromyopathies to occur. In analogy to these diseases the neurological symptoms in XP might be explained by abnormal mitochondria.
...
PMID:Enhanced expression of mitochondrial genes in xeroderma pigmentosum fibroblast strains from various complementation groups. 839 67

Linear 75mer double-stranded DNA containing a single pyrimidine dimer at a unique site was used to investigate pyrimidine dimer-dependent endonuclease activities from human cells. HeLaS3 cell extract incised the target DNA at the fourth phosphodiester linkage 3' to the pyrimidine dimer. However, incision of the DNA at 5' side of the pyrimidine dimer was not detected. The incision was also detected in cell extracts prepared from other excision repair-proficient cell lines. Incision was detected only on the DNA strand containing a pyrimidine dimer in the presence of poly(dI-dC)-poly(dI- dC) double strand. The reaction required Mg2+ but not ATP. The extract prepared from excision repair-deficient xeroderma pigmentosum (XP) cells belonging to the complementation group A was unable to incise the DNA. Extracts from the complementation groups C, D, and G incised the DNA very weakly at the third phosphodiester linkage 3' to the pyrimidine dimer, a site different from that incised by normal human cell extract. These results suggest that the observed incision reaction is associated with excision repair in human cells.
...
PMID:Human nucleotide excision nuclease incises synthetic double-stranded DNA containing a pyrimidine dimer at the fourth phosphodiester linkage 3' to the pyrimidine dimer. 843 33

The repair of X-ray-induced DNA damage related to the proliferating cell nuclear antigen (PCNA) was characterized in human diploid fibroblasts by an indirect immunofluorescence method. PCNA staining induced by X rays was lost after DNase I treatment but not after RNase treatment. The staining was not induced when ATP was depleted or the temperature was lowered to 0 degrees C during the X irradiation. When cells were incubated at 37 degrees C after X irradiation, PCNA staining diminished gradually and was almost entirely absent 12-15 h later. On the other hand, PCNA staining persisted during aphidicolin treatment even 20 h after X irradiation. Induction of PCNA staining was not affected by the aphidicolin treatment. Cycloheximide treatment did not affect induction of the staining either, but did inhibit the disappearance of the staining. There was no difference in the staining pattern and time course of PCNA staining after X irradiation between normal and xeroderma pigmentosum group A (XP-A) cells. These results imply that PCNA-dependent, aphidicolin-sensitive DNA polymerases may be involved in repair of X-ray-induced DNA damage in vivo, but the repair initiation step could be different from that of nucleotide excision repair initiated by XP proteins.
...
PMID:Characterization of X-ray-induced immunostaining of proliferating cell nuclear antigen in human diploid fibroblasts. 853 40

During nucleotide excision repair in human cells, a damaged DNA strand is cleaved by two endonucleases, XPG on the 3' side of the lesion and ERCC1-XPF on the 5' side. These structure-specific enzymes act at junctions between duplex and single-stranded DNA. ATP-dependent formation of an open DNA structure of approximately 25 nt around the adduct precedes this dual incision. We investigated the mechanism of open complex formation and find that mutations in XPB or XPD, the DNA helicase subunits of the transcription and repair factor TFIIH, can completely prevent opening and dual incision in cell-free extracts. A deficiency in XPC protein also prevents opening. The absence of RPA, XPA or XPG activities leads to an intermediate level of strand separation. In contrast, XPF or ERCC1-defective extracts open normally and generate a 3' incision, but fail to form the 5' incision. This same repair defect was observed in extracts from human xeroderma pigmentosum cells with an alteration in the C-terminal domain of XPB, suggesting that XPB has an additional role in facilitating 5' incision by ERCC1-XPF nuclease. These data support a mechanism in which TFIIH-associated helicase activity and XPC protein catalyze initial formation of the key open intermediate, with full extension to the cleavage sites promoted by the other core nucleotide excision repair factors. Opening is followed by dual incision, with the 3' cleavage made first.
...
PMID:Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. 935 36

The p89/xeroderma pigmentosum complementation group B (XPB) ATPase-helicase of transcription factor IIH (TFIIH) is essential for promoter melting prior to transcription initiation by RNA polymerase II (RNAPII). By studying the topological organization of the initiation complex using site-specific protein-DNA photo-cross-linking, we have shown that p89/XPB makes promoter contacts both upstream and downstream of the initiation site. The upstream contact, which is in the region where promoter melting occurs (positions -9 to +2), requires tight DNA wrapping around RNAPII. The addition of hydrolyzable ATP tethers the template strand at positions -5 and +1 to RNAPII subunits. A mutation in p89/XPB found in a xeroderma pigmentosum patient impairs the ability of TFIIH to associate correctly with the complex and thereby melt promoter DNA. A model for open complex formation is proposed.
...
PMID:Mechanism of promoter melting by the xeroderma pigmentosum complementation group B helicase of transcription factor IIH revealed by protein-DNA photo-cross-linking. 1102 86

TFIIH is a multifunctional RNA polymerase II general initiation factor that includes two DNA helicases encoded by the Xeroderma pigmentosum complementation group B (XPB) and D (XPD) genes and a cyclin-dependent protein kinase encoded by the CDK7 gene. Previous studies have shown that the TFIIH XPB DNA helicase plays critical roles not only in transcription initiation, where it catalyzes ATP-dependent formation of the open complex, but also in efficient promoter escape, where it suppresses arrest of very early RNA polymerase II elongation intermediates. In this report, we present evidence that ATP-dependent TFIIH action in transcription initiation and promoter escape requires distinct regions of the DNA template; these regions are well separated from the promoter region unwound by the XPB DNA helicase and extend, respectively, approximately 23-39 and approximately 39-50 bp downstream from the transcriptional start site. Taken together, our findings bring to light a role for promoter DNA in TFIIH action and are consistent with the model that TFIIH translocates along promoter DNA ahead of the RNA polymerase II elongation complex until polymerase has escaped the promoter.
...
PMID:TFIIH action in transcription initiation and promoter escape requires distinct regions of downstream promoter DNA. 1133 64

The ERCC2 protein is an evolutionary conserved ATP-dependent helicase that is associated with a TFIIH transcription factor complex and plays an important role in nucleotide excision repair. Mutations in this gene are responsible for xeroderma pigmentosum and also for Cocayne syndrome and trichothiodystrophy. Several single nucleotide polymorphisms have been identified in the ERCC2 locus. Among them, a G23591A polymorphism in the codon 312 results in an Asp --> Asn substitution in a conserved region and a A35931C polymorphism in the codon 751 results in a Lys --> Gln substitution. Because these polymorphisms have been associated with an increased risk for several types of cancers, we carried out an hospital based case-control study in a Caucasian Portuguese population to evaluate the potential role of these polymorphisms on the individual susceptibility to thyroid cancer. The results obtained did not reveal a significant association between each individual polymorphism studied (G23591A and A35931C) and an increased thyroid cancer risk, but individuals homozygous for non-wild-type variants are overrepresented in patients group. The evaluation of the different haplotypes generated by these polymorphisms showed that individuals simultaneously homozygous for rare variants of both polymorphisms have an increased risk for thyroid cancer [adjusted odds ratio (OR) 3.084; 95% confidence interval (95% CI), 1.347-7.061; P = 0.008] and for papillary thyroid-type tumors (adjusted OR, 2.997; 95% CI, 1.235-7.272; P = 0.015) but not for follicular thyroid-type tumors. These results suggest that genetic polymorphisms in this gene might be associated with individual susceptibility towards thyroid cancer, mainly papillary-type tumors, but larger studies are required to confirm these results.
...
PMID:Association of polymorphisms in ERCC2 gene with non-familial thyroid cancer risk. 1621 24

DNA helicases are required for virtually every aspect of DNA metabolism, including replication, repair, recombination and transcription. A comprehensive description of these essential biochemical processes requires detailed understanding of helicase mechanisms. These enzymes are ubiquitous, having been identified in viruses, prokaryotes and eukaryotes. Disease states, such as xeroderma pigmentosum, Cockayne's syndrome, Bloom's syndrome and Werner's syndrome, have been linked to defects in specific genes coding for DNA helicases. Helicases have been placed into different subfamilies based on sequence comparison. The largest subgroups are termed superfamily 1 and superfamily 2. A proposed mechanism for helicases in these classes has been described in terms of an 'inchworm model'. The inchworm model includes conformational changes driven by ATP binding and hydrolysis that allow unidirectional translocation along DNA. A monomeric form of the enzyme is proposed to have two DNA-binding sites that enable sequential steps of DNA binding and release. Significant differences exist between helicases in important aspects of the models such as the oligomerization state of the enzyme with some helicases functioning as monomers, some as dimers and others as higher-order oligomers.
...
PMID:DNA unwinding and protein displacement by superfamily 1 and superfamily 2 helicases. 1693 80

Helicases often achieve functional specificity through utilization of unique structural features incorporated into an otherwise conserved core. The archaeal Rad3 (xeroderma pigmentosum group D protein (XPD)) helicase is a prototypical member of the Rad3 family, distinct from other related (superfamily II) SF2 enzymes because of a unique insertion containing an iron-sulfur (FeS) cluster. This insertion may represent an auxiliary domain responsible for modifying helicase activity or for conferring specificity for selected DNA repair intermediates. The importance of the FeS cluster for the fine-tuning of Rad3-DNA interactions is illustrated by several clinically relevant point mutations in the FeS domain of human Bach1 (FancJ) and XPD helicases that result in distinct disease phenotypes. Here we analyzed the substrate specificity of the Rad3 (XPD) helicase from Ferroplasma acidarmanus (FacRad3) and probed the importance of the FeS cluster for Rad3-DNA interactions. We found that the FeS cluster stabilizes secondary structure of the auxiliary domain important for coupling of single-stranded (ss) DNA-dependent ATP hydrolysis to ssDNA translocation. Additionally, we observed specific quenching of the Cy5 fluorescent dye when the FeS cluster of a bound helicase is positioned in close proximity to a Cy5 fluorophore incorporated into the DNA molecule. Taking advantage of this Cy5 quenching, we developed an equilibrium assay for analysis of the Rad3 interactions with various DNA substrates. We determined that the FeS cluster-containing domain recognizes the ssDNA-double-stranded DNA junction and positions the helicase in an orientation consistent with duplex unwinding. Although it interacts specifically with the junction, the enzyme binds tightly to ssDNA, and the single-stranded regions of the substrate are the major contributors to the energetics of FacRad3-substrate interactions.
...
PMID:The iron-containing domain is essential in Rad3 helicases for coupling of ATP hydrolysis to DNA translocation and for targeting the helicase to the single-stranded DNA-double-stranded DNA junction. 1802 58


<< Previous 1 2 3 4 5 Next >>

---