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)

A mathematical model is used to analyze mutant spectra for large mutations induced by low-LET radiation. The model equations are based mainly on two-break misrejoining that leads to deletions or translocations. It is assumed, as a working hypothesis, that the initial damage induced by low-LET radiation is located randomly in the genome. Specifically, we analyzed data for two hemizygous loci: CD59- mutants, mainly very large-scale deletions (>3 Mbp), in human-hamster hybrid cells, and data from the literature on those HPRT- mutants which involve at least deletion of the whole gene, and often of additional flanking markers (approximately 50-kbp to approximately 4.4-Mbp deletions). For five data sets, we estimated f, the probability that two given breaks on the same chromosome will misrejoin to make a deletion, as a function of the separation between the breaks. We found that f is larger for nearby breaks than for breaks that are more widely separated; i.e., there is a "proximity effect". For acute irradiation, the values of f determined from the data are consistent with the corresponding break misrejoining parameters found previously in quantitative modeling of chromosome aberrations. The value of f was somewhat smaller for protracted irradiation than for acute irradiation at a given total dose; i.e., the mutation data show a decrease that was smaller than expected for dose protraction by fractionation or low dose rate.
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PMID:Large-mutation spectra induced at hemizygous loci by low-LET radiation: evidence for intrachromosomal proximity effects. 1160 68

It has been reported that X-ray induced HPRT- mutation in cultured human cells is prevented by ascorbate added after irradiation. Mutation extinction is attributed to neutralization by ascorbate, of radiation-induced long-lived radicals (LLR) with half-lives of several hours. We here show that post-irradiation treatment with ascorbate (5 mM added 30 min after radiation) reduces, but does not eliminate, the induction of CD59- mutants in human-hamster hybrid A(L) cells exposed to high-LET carbon ions (LET of 100 KeV/microm). RibCys, [2(R,S)-D-ribo-1',2',3',4'-Tetrahydroxybutyl]-thiazolidene-4(R)-ca riboxylic acid] (4 mM) gave a similar but lesser effect. The lethality of the carbon ions was not altered by these chemicals. Preliminary data are presented that ascorbate also alters the spectrum of CD59- mutations induced by the carbon beam, mainly by reducing the incidence of small mutations and mutants displaying transmissible genomic instability (TGI), while large mutations are unaffected. Our results suggest that LLR are important in initiating TGI.
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PMID:Ascorbate, added after irradiation, reduces the mutant yield and alters the spectrum of CD59- mutations in A(L) cells irradiated with high LET carbon ions. 1279 67

Miazaki, Watanabe, Kumagai and their colleagues reported that induction of HPRT(-) mutants by X-rays in cultured human cells was prevented by ascorbate added 30min after irradiation. They attributed extinction of induced mutation to neutralization by ascorbate of radiation-induced long-lived mutagenic radicals (LLR), found using spectroscopy to have half-lives of minutes or hours. We find that post-irradiation treatment with ascorbate reduces, but does not eliminate, induction of CD59(-) mutants in human-hamster hybrid A(L) cells exposed to high-LET carbon-ions (LET of 100KeV/microm). A(L) cells contain a standard set of Chinese hamster ovary (CHO) chromosomes and a single copy of human chromosome 11 containing the CD59 gene which encodes the CD59 cell surface antigen, a convenient marker for mutation. RibCys [2(R, S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-carboxylic acid] a 'prodrug' of l-cysteine which also scavenges LLR, had a similar but lesser effect on induced mutation. DMSO, which scavenges classical radicals like H* and OH* but not LLR, also reduced mutation, but only when it was present during irradiation. The lethality of carbon-ions was not altered by ascorbate, RibCys no matter when added. Post-radiation addition of ascorbate and RibCys also affected the quality of CD59(-) mutations induced by carbon-ions. The major change in mutant spectra was a reduction in the prevalence of small, intragenic mutations (mutations not detected by PCR) and in the prevalence of unstable, complicated mutants, which display high levels of persistent chromosomal instability. Thus, ascorbate and RibCys may suppress some kinds of mutations induced by ionizing radiation including those displaying aspects of radiation-induced genomic instability. Countering the effects of both classical radicals and LLR may be important in preventing genetic diseases.
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PMID:A role for long-lived radicals (LLR) in radiation-induced mutation and persistent chromosomal instability: counteraction by ascorbate and RibCys but not DMSO. 1522 98