Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.4.2.7 (adenine phosphoribosyltransferase)
 692 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutional loss or inactivation of one copy of a tumor-suppressor gene, as exemplified by hereditary retinoblastoma, increases the propensity for malignancies by reducing the number of events necessary for the complete loss of the negative regulatory function. We developed a selectable mutation assay employing a human lymphoblastoid cell line (LCL) derived from a heterozygous carrier of 2,8-dihydroxyadenine urolithiasis, adenine phosphoribosyltransferase (APRT) deficiency, for dissecting the second step in loss-of-function mutations and for determining the potential of physical and chemical agents for producing such mutations. The mode of mutational events arising in the wild-type allele of the functionally heterozygous APRT gene resembled that reported for tumor-suppressor genes in malignancies in that mitotic non-disjunctions or recombinations as well as deletions prevailed. Ultraviolet light (UV) was much less efficient in inducing these types of mutations than ionizing radiation. A group of autosomal recessive cancer-prone diseases, including xeroderma pigmentosum (XP), has been characterized as being more susceptible to genomic insults, owing to some defects in DNA processing, such as replication, repair, or recombination. This increased genomic instability may accelerate the gain-of-function mutation at a proto-oncogene and/or the loss-of-function mutation at a tumor-suppressor gene. XP complementation group A (XP-A) LCLs were extremely sensitive to UV-mutagenesis at the hypoxanthine phosphoribosyltransferase (HPRT) locus even at equicytotoxic doses. Some unique mechanism may operate in UV-mutagenesis in XP-A. We have succeeded for the first time in rendering XP-A cells tumorigenic in athymic mice by applying multiple exposures to UV and subsequent treatment with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular bases for hereditary cancer-prone diseases. 129 55

Spontaneous deletion mutants can be isolated from CHO cell lines heterozygous at the adenine phosphoribosyltransferase locus at frequencies up to 10(-4), i.e., about 100-fold higher than spontaneous point mutations. Indirect evidence has suggested that most deletions were in the megabase range. We have fully characterized one such mutant, Del 155, and shown that it resulted from an illegitimate recombination that took place between overlapping tetranucleotides. Comparisons with sequences of other deletions at various loci revealed a number of similarities, most striking of which was a CHI-like motif found within 6 bp of the upstream breakpoint of Del 155 and breakpoints of 8/21 previously described short deletions at the CHO aprt locus. Homology also existed between the downstream breakpoint of Del 155 and breakpoints of retinoblastoma gene deletions (3/6 cases) and also a 20-bp stretch of an Alu sequence in which breakpoints at the low-density lipoprotein receptor locus have been shown to cluster. The magnitude of the deletion event in Del 155 was assessed by pulsed field (PF) gel analysis and found to be at least 2100 kb long. PF analysis also indicated that the downstream breakpoint was near a region of structural differences between the two chromosomes carrying apart. These structural differences were probably not implicated in the mechanism of the high frequency event, since no indication of breakpoint clustering among a large collection of mutants was found either by conventional or PF electrophoretic analyses.
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PMID:A very large spontaneous deletion at aprt locus in CHO cells: sequence similarities with small aprt deletions. 199 42

Expression of a recessive phenotype can occur by a number of different mechanisms, such as chromosomal deletion, recombination, and intragenic frameshift mutation or base substitution. To examine the contribution of different mutational events, we isolated and characterized a human fibroblast cell line heterozygous at the adenine phosphoribosyltransferase (APRT) locus. Cells that subsequently lost APRT activity were selected, cloned, and analyzed for the mechanisms contributing to the loss of APRT activity. Loss of APRT activity occurred at a rate of 7.8 x 10(-5) per allele per cell generation. Molecular analysis of DNA from 21 independent APRT- clones demonstrated that 62% of mutants had lost the functional allele and that the rest had incurred intragenic mutations. Loss of the functional allele was frequently accompanied by loss of the proximal marker D16S77 but not the more distant proximal marker D16S4, indicating that a high frequency of mitotic recombination or deletion occurred at the region between D16S77 and D16S4 on chromosome 16. Loss of APRT activity in the remaining 38% of the clones was predominantly due to point mutations. These data demonstrate that the mechanisms for loss of heterozygosity at the APRT locus are similar to those found in retinoblastoma and other tumors. The autosomal location of the APRT gene and the ease with which its phenotype can be selected make this gene useful for modeling mutational events at loci important to carcinogenesis.
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PMID:Loss of heterozygosity: the most frequent cause of recessive phenotype expression at the heterozygous human adenine phosphoribosyltransferase locus. 821 32