Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endometrial tumor cell line HHUA carries mutations in two mismatch repair (MMR) genes MSH3 and MSH6. We have established an MSH3-deficient HHUA/chr.2 cell line by introducing human chromosome 2, which carries wild-type MSH6 and MSH2 genes, to HHUA cells. Introduction of chromosome 2 to HHUA cells partially restored G:G MMR activity to the cell extract and reduced the frequency of mutation at the hypoxanthine-guanine phosphoribosyltransferase (hprt*) locus to about 3% that of the parental HHUA cells, which is five-fold the frequency in MMR-proficient cells, indicating that the residual mutator activity in HHUA/chr.2 is due to an MSH3-deficiency in these cells. The spectrum of mutations occurring at the HPRT locus of HHUA/chr.2 was determined with 71 spontaneous 6TG(r) clones. Base substitutions and +/-1 bp frameshifts were the major mutational events constituting, respectively, 54% and 42% of the total mutations, and more than 70% of them occurred at A:T sites. A possible explanation for the apparent bias of mutations to A:T sites in HHUA/chr.2 is haploinsufficiency of the MSH6 gene on the transferred chromosome 2. Comparison of the mutation spectra of HHUA/chr.2 with that of the MSH6-deficient HCT-15 cell line [S. Ohzeki, A. Tachibana, K. Tatsumi, T. Kato, Carcinogenesis 18 (1997) 1127-1133.] suggests that in vivo the MutSalpha (MSH2:MSH6) efficiently repairs both mismatch and unpaired extrahelical bases, whereas MutSbeta (MSH2:MSH3) efficiently repairs extrahelical bases and repairs mismatch bases to a limited extent.
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PMID:Mutation spectrum of MSH3-deficient HHUA/chr.2 cells reflects in vivo activity of the MSH3 gene product in mismatch repair. 1075 99

The DLD-1 human colon cancer cell line displays an elevated spontaneous mutation rate. Since DLD-1 carries frameshift mutations in both alleles of the MSH6 gene and missense mutations in the POLD1 gene, either or both of these mutations were suggested to be involved in this mutator phenotype. Therefore, we examined the effect of exogenous wild-type MSH6 and POLD1 expression on the spontaneous mutation rate at the HPRT locus in DLD-1 cells. POLD1 genotypes were first determined, since four POLD1 missense mutations were previously reported in DLD-1 cells. Sequencing analyses on the genomic DNA and cDNA of the POLD1 gene revealed that DLD-1 cells are a mixture of two distinct sublines with regard to POLD1 genotypes. Moreover, the wild-type POLD1 allele was not present in either of the two DLD-1 sublines. We next established MSH6- and POLD1-transfected DLD-1 clones from both sublines, respectively. The two DLD-1 sublines exhibited HPRT mutation rates of 4.8 x 10(-6) and 5.4 x 10(-6) mutations/cell/generation. The mutation rates were more than 4-fold decreased in both of the MSH6-transfected DLD-1 clones examined, while they were not significantly decreased in three of four POLD1-transfected DLD-1 clones. Thus, it was indicated that mutations in the MSH6 gene, and not in the POLD1 gene, are primarily responsible for the elevated mutation rates in DLD-1 cells.
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PMID:Effect of exogenous MSH6 and POLD1 expression on the mutation rate of the HPRT locus in a human colon cancer cell line with mutator phenotype, DLD-1. 1476 55

The KDM4 family of lysine demethylases consists of five members, KDM4A, -B and -C that demethylate H3K9me2/3 and H3K36me2/3 marks, while KDM4D and -E demethylate only H3K9me2/3. Recent studies implicated KDM4 proteins in regulating genomic instability and carcinogenesis. Here, we describe a previously unrecognized pathway by which hyperactivity of KDM4 demethylases promotes genomic instability. We show that overexpression of KDM4A-C, but not KDM4D, disrupts MSH6 foci formation during S phase by demethylating its binding site, H3K36me3. Consequently, we demonstrate that cells overexpressing KDM4 members are defective in DNA mismatch repair (MMR), as evident by the instability of four microsatellite markers and the remarkable increase in the spontaneous mutations frequency at the HPRT locus. Furthermore, we show that the defective MMR in cells overexpressing KDM4C is mainly due to the increase in its demethylase activity and can be mended by KDM4C downregulation. Altogether, our data suggest that cells overexpressing KDM4A-C are defective in DNA MMR and this may contribute to genomic instability and tumorigenesis.
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PMID:Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway. 2577 Jan 86