| Carcinogens stimulate intrachromosomal homologous recombination at an endogenous locus in human diploid fibroblasts. | |
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MedLine Citation:
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PMID: 9506887 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mitotic recombination is believed to play an important role in the development of many cancers. An improved system has been developed to detect reversion of an intragenic DNA duplication, as a model for intrachromosomal homologous recombination. The 'LNtd' strain of human fibroblasts, derived from a Lesch-Nyhan donor, produces no detectable hypoxanthine phosphoribosyltransferase (HPRT) activity due to a 13.7-kilobase-pair DNA insertion duplicating exons 2 and 3 of the HPRT locus. These cells are therefore sensitive to selection in HAT medium, against cells lacking functional HPRT enzyme. Clonal reversion to HAT resistance occurs spontaneously at 1-3 x 10(-5)/cell/generation, and can be induced by brief exposure to a variety of carcinogenic agents. Six known carcinogens, including two (diethylstilbestrol and nickel chloride) which were non-mutagenic in Salmonella by Ames HIS-reversion tests, showed dose-dependent induction of LNtd reversion by a maximum of 2.4- to > 11-fold over controls (each p < 0.01). In contrast, 5 non-carcinogenic agents, including two 'Ames-positive' chemicals, sodium azide and 8-hydroxyquinoline, evoked no more than a 1.7-fold increase in reversion (not significant). The molecular events associated with reversion to HAT-resistance were characterized, relative to the parental strain, in HATR clones derived from either untreated or carcinogen-treated cells. Both the intron-3:intron-1 junction situated between the duplicated HPRT segments in LNtd cells (amplified by polymerase chain reaction), and a restriction fragment corresponding to the duplicated HPRT DNA (assessed by Southern-blot hybridization), were lost from the majority of HATR revertant clones, whether they arose spontaneously or following exposure to Cr(VI) or ultraviolet light. These results imply that HATR reversion is induced in LNtd cells by carcinogenic treatments, through a mechanism consistent with homologous recombination, and is highly concordant with induction of in vivo carcinogenesis by the same agents. |
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Authors:
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J Li; R Ayyadevera; R J Shmookler Reis |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Mutation research Volume: 385 ISSN: 0027-5107 ISO Abbreviation: Mutat. Res. Publication Date: 1997 Dec |
Date Detail:
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Created Date: 1998-03-27 Completed Date: 1998-03-27 Revised Date: 2004-11-17 |
Medline Journal Info:
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Nlm Unique ID: 0400763 Medline TA: Mutat Res Country: NETHERLANDS |
Other Details:
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Languages: eng Pagination: 173-93 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aminopterin
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pharmacology Carcinogens / pharmacology* Cells, Cultured Chromosome Mapping Clone Cells Culture Media DNA / analysis, genetics DNA Damage / drug effects, radiation effects Dose-Response Relationship, Drug Fibroblasts Humans Hypoxanthine Phosphoribosyltransferase / genetics*, metabolism* Lesch-Nyhan Syndrome Multigene Family* Mutagenicity Tests* Polymerase Chain Reaction Polymorphism, Restriction Fragment Length Recombination, Genetic / drug effects*, radiation effects Ultraviolet Rays |
| Chemical | |
Reg. No./Substance:
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0/Carcinogens; 0/Culture Media; 54-62-6/Aminopterin; 9007-49-2/DNA; EC 2.4.2.8/Hypoxanthine Phosphoribosyltransferase |
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