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)

Mutations in mammalian genomes are the result of several mutagenic processes that are intrinsic to cell metabolism. Analysis of the mutation spectrum of a chromosomal gene is a valuable tool for assessing the contribution of these mechanisms to mutagenesis in the cell. We have studied the specificity of mutations induced by various mutagens in a cDNA hprt gene integrated in a chromosome of a mouse cell line. To understand the mechanisms underlying mammalian cell mutagenesis, we compiled a list of more than 250 sequenced hprt mutations that arose spontaneously or were induced by mutagens, and compared it with the published mutation data. There are at least two distinct processes of mutagenesis in eukaryotic cells: one is mispairing, while another is errors in translesion synthesis. The alkylating agent methylnitrosourea causes G:T mispairing; consequently, most mutations it induces are G to A transitions. The second process can occur spontaneously or be caused by exposure to X-rays, Trp-P2, a tryptophan pyrolysate, or acetylaminofluorene. A variety of premutagenic lesions are produced in DNA by these mutagens, but spectra of the mutations resemble each other, especially in the high frequency of deletions at the sites of short direct repeats. The slippage--misalignment mechanism accounted well for the greater part of the observed deletions. A similar spectrum of mutations was observed in the tumor suppressor gene APC from colorectal tumors; about 40% are deletions at the sites of short repeats. These findings led us to propose that slippage--misalignment is an ubiquitous mechanism of mutagenesis and is responsible for a significant proportion of spontaneous mutations in mammalian cells.
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PMID:Slippage--misalignment: to what extent does it contribute to mammalian cell mutagenesis? 783 71

Polycyclic aromatic hydrocarbons (PAH) and nitrated polycyclic aromatic compounds (nitro-PAC) have been found to be mutagenic in bacterial and human cells as well as carcinogenic in rodents. In this investigation, the genotoxic effects of 3-nitrobenzanthrone (3NB) and a mixture of nitropyrene lactones (NPLs) were determined using forward mutation assays performed in two human B-lymphoblastoid cell lines, MCL-5 and h1A1v2, which are responsive to the nitro-PAC class of compounds. Mutagenicity of the compounds was determined at the heterozygous tk locus and the hemizygous hprt locus, thus, identifying both large-scale loss of heterozygosity (LOH) events as well as intragenic mutagenic events. Genotoxicity was also determined using the CREST modified micronucleus assay, which detects chromosomal loss and breakage events. Results indicate 3NB is an effective human cell mutagen, significantly inducing mutations at the tk and hprt loci in both cell lines, and inducing micronuclei in the h1A1v2 cell line. The NPL isomers are also mutagenic, inducing mutations at the two loci as well as micronuclei in both cell lines. Because of their mutagenic potencies and their presence in ambient air, further assessments should be made of human exposures to these nitro-PAC and the potential health risks involved.
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PMID:The genotoxicity of 3-nitrobenzanthrone and the nitropyrene lactones in human lymphoblasts. 1111 2

Anaphase promoting complex/cyclosome (APC/C)-mediated proteolysis is essential for chromosome segregation, mitotic exit, and G1 entry. Here, we show the importance of APC/C in the control of dTTP pool size in mammalian cells. Two enzymes, thymidine kinase 1 (TK1) and thymidylate kinase (TMPK), involved in dTTP formation are the targets of the APC/C pathway. We demonstrate that TMPK is recognized and degraded by APC/C-Cdc20/Cdh1-mediated pathways from mitosis to the early G1 phase, whereas TK1 is targeted for degradation by APC/C-Cdh1 after mitotic exit. Overexpression of wild-type TK1 and TMPK induces a four- to fivefold increase in the cellular dTTP pool without promoting spontaneous mutations in the hprt (hypoxanthine-guanine phosphoribosyl transferase) gene. In contrast, coexpression of nondegradable TK1 and TMPK expands the dTTP pool size 10-fold accompanied by a drastic dNTP pool imbalance. Most interestingly, disruption of APC/C proteolysis of TK1 and TMPK leads to growth retardation and a striking increase in gene mutation rate. We conclude that down-regulation of dTTP pool size by the APC/C pathway during mitosis and the G1 phase is an essential means to maintain a balanced dNTP pool and to avoid genetic instability.
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PMID:Control of dTTP pool size by anaphase promoting complex/cyclosome is essential for the maintenance of genetic stability. 1610 19