Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have determined the frequency and spectrum of spontaneous mutations at the hprt locus in LoVo, HCT116, LS180 and DLD-1 colon carcinoma cell lines exhibiting microsatellite genetic instability. Each cell line has a different mutator gene. LoVo and HCT116 cells have mutated hMSH2 and hMLH1 genes, respectively, which account for the majority of hereditary non-polyposis colorectal cancer (HNPCC). LS180 cells are wild type for these genes and also for hPMS1 and hPMS2 mismatch repair genes. DLD-1 cells harbor a mutated GTBP mismatch binding factor and a mutated DNA Polymerase delta. The mutation rate at the hprt locus was several hundred fold higher in these cell lines relative to control cell lines without microsatellite instability. The mutations were frameshifts (deletions and insertions of a single nucleotide in short repeats) and single base substitutions (transversions and transitions). Some mutations were shared by these four cell lines. However, every cell line also exhibited a distinctive spectrum of mutations suggesting that each mutator gene induces a particular mutator phenotype. These results also suggest that the frequency and spectrum of somatic mutations in tumor cells of the microsatellite mutator phenotype may have diagnostic applications to discriminate among the diverse underlying mutator genes.
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PMID:Differences in the spectrum of spontaneous mutations in the hprt gene between tumor cells of the microsatellite mutator phenotype. 864 58

Spectra of spontaneous mutations at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in colon carcinoma cell lines HCT116 and HCT-15 deficient in mismatch repair and displaying mutator phenotypes were determined. HCT116 and HCT-15 cells, respectively, harbour a mutation in the mismatch repair gene hMLH1 and GTBP. The mutation frequency at the hprt locus in both cell lines was elevated by about two orders, but the microsatellite instability in HCT116 cells was one order higher than in HCT-15 cells. Except for one mutant of HCT-15, all the mutations (114/115) were point mutations; base substitutions of various types and frameshifts (deletions/insertions of less than a few bases, predominantly of +/-1 bp). Base substitutions (57%) and frameshifts (43%) occurred at a comparable rate in HCT116, whereas base substitutions (92%) were the major mutational events in HCT-15. Most frameshifts in HCT116 occurred at sites of monotonous or short tandem repeating sequences, and two of these sites, where there was a run of six Gs and four As, were hot spots. Three hot spot sites of base substitutions were found in HCT-15; two of them at splice acceptor sites, the other at the CpG site shared with HCT116. The distinct mutation spectra of the HCT116 and HCT-15 cell lines may reflect functional differences in the hMLH1 and GTBP gene products in mismatch repair. The gene product GTBP may be involved in the preferential repair of base mismatches, and MLH1 in the repair of both base mismatches and deletions/insertions of less than a few bases. These results suggest that mismatch repair deficiency affects the microsatellite stability as widely reported in colorectal tumour cells, but that it may not severely affect chromosome integrity as the karyotypes of these tumour cells are, unlike other tumour cells, relatively stable.
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PMID:Spectra of spontaneous mutations at the hprt locus in colorectal carcinoma cell lines defective in mismatch repair. 921 93

The spectrum of mutations was determined at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in the human uterine tumor cell line HEC-1-A which is defective in the mismatch repair gene hPMS2. The mutation frequency at the hprt locus in HEC-1-A was about two orders higher than that in wild type repair-proficient cells. The fifty-eight mutations detected were exclusively point mutations, with frameshifts of one base deletion/addition predominating (66%) the remaining were base substitutions. All the frameshift mutations occurred at sites of monotonous repeating sequences, including six consecutive guanine bases site which was the hot spot for the addition of one G that contributed 60% of the total mutations. Although the observed specificity of mutations in HEC-1-A apparently resembled that of the hMLH1-deficient cell line HCT116 [Ohzeki, S., Tachibana, A., Tatsumi, T., Kato, T., 1997. Spectra of spontaneous mutations at the hprt locus in colorectal carcinoma cell lines defective in mismatch repair. Carcinogenesis, 18, 1127-1133.], the pronounced increase of +/-1 bp frameshifts and the reduced incidence of C-->T transitions at the CpG site suggest that the hPMS2 gene product may have an additional function in the mismatch repair process independent of it's role in the hMutLalpha heterodimer.
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PMID:Specificity of mutations in the PMS2-deficient human tumor cell line HEC-1-A. 983 64

Genetic or epigenetic inactivation of one of the DNA mismatch repair (MMR) genes in tumor precursor cells causes a profound mutator phenotype, known as the microsatellite mutator phenotype (MMP). This mutator phenotype induces mutations not only in cancer genes that drive tumorigenesis but also in other DNA repair genes. The functional significance of these successive DNA repair gene mutations, however, has not been substantiated. Here we show that the concomitant inactivation of two DNA MMR genes (hMLH1 and hMSH6) increases the mutator phenotype. We isolated cell clones of the SW48 MMP-positive cell line with either active or inactive hMSH6. All of these clones lacked expression of hMLH1 because of promoter hypermethylation. Compared with inactivation of hMLH1 alone, the additional inactivation of hMSH6 produced a higher mutation rate and a different spectrum of mutations in the endogenous hprt gene. These results confirm our model that the mutator phenotype can increase during tumorigenesis by the consecutive inactivation of different members of the DNA MMR system. Thus, a stronger mutator phenotype accelerates the accumulation of mutations in target cancer genes, which, in turn, speeds up tumor progression. The results of this study also have significant impact on our understanding of the mechanism of DNA MMR.
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PMID:Functional significance of concomitant inactivation of hMLH1 and hMSH6 in tumor cells of the microsatellite mutator phenotype. 1174 74

Oxidation is a common form of DNA damage to which purines are particularly susceptible. We previously reported that oxidized dGTP is potentially an important source of DNA 8-oxodGMP in mammalian cells and that the incorporated lesions are removed by DNA mismatch repair (MMR). MMR deficiency is associated with a mutator phenotype and widespread microsatellite instability (MSI). Here, we identify oxidized deoxynucleoside triphosphates (dNTPs) as an important cofactor in this genetic instability. The high spontaneous hprt mutation rate of MMR-defective msh2(-/-) mouse embryonic fibroblasts was attenuated by expression of the hMTH1 protein, which degrades oxidized purine dNTPs. A high level of hMTH1 abolished their mutator phenotype and restored the hprt mutation rate to normal. Molecular analysis of hprt mutants showed that the presence of hMTH1 reduced the incidence of mutations in all classes, including frameshifts, and also implicated incorporated 2-oxodAMP in the mutator phenotype. In hMSH6-deficient DLD-1 human colorectal carcinoma cells, overexpression of hMTH1 markedly attenuated the spontaneous mutation rate and reduced MSI. It also reduced the incidence of -G and -A frameshifts in the hMLH1-defective DU145 human prostatic cancer cell line. Our findings indicate that incorporation of oxidized purines from the dNTP pool may contribute significantly to the extreme genetic instability of MMR-defective human tumors.
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PMID:The oxidized deoxynucleoside triphosphate pool is a significant contributor to genetic instability in mismatch repair-deficient cells. 1467 78