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