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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Moschel, R. C. Hughes, S. H. Mitra, G. Barbacid, M. Pauly, G. T. Kumar, R. Pei, G. K. |
| Description | Author Affiliation: Mitra G ( Developmental Oncology, National Cancer Institute-Frederick Cancer Research Facility, MD 21701.); |
| Abstract | We have designed an Ha-ras/thymidine kinase (TK) cassette that permits the incorporation of chemically synthesized adducts within specific domains of the rat Ha-ras protooncogene. This cassette has been used to evaluate the mutagenicity of O6-substituted guanine residues, including O6-methylguanine and O6-benzylguanine, incorporated within the 12th codon of this locus. Mutations were monitored by the ability of these modified Ha-ras DNAs to transform Rat4 TK-cells. Our results indicate that both types of O6-substituted guanines are substantially mutagenic, although the methyl substituent induced a 2-fold higher percentage of transformed Rat4 TK+ colonies than its bulkier benzyl analogue. Interestingly, the mutagenicity of both O6-substituted guanines was found to be independent of their relative position within codon 12, therefore suggesting that the specific activation of Ha-ras oncogenes by GGA----GAA mutations in tumors induced by methylating carcinogens might be due to differences in the accessibility of these guanine residues to the carcinogen rather than to a differential rate of repair. Molecular analysis of the mutations induced by these O6-substituted guanines indicated that O6-methylguanine exclusively induced G----A transitions. In contrast, O6-benzylguanine produced G----C and G----T transversions in addition to G----A transitions. These results suggest that O6-methylguanine and its bulkier analogue O6-benzylguanine may induce mutagenesis by different mechanisms. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 22 |
| Volume Number | 86 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 1989-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Genes, Ras Guanine Analogs & Derivatives Metabolism Mutation Alkylation Animals Cell Line DNA-Directed DNA Polymerase Escherichia Coli Genetics Gene Amplification Molecular Sequence Data Oligonucleotide Probes Plasmids Restriction Mapping Transfection Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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