The structure of mutation in mammalian cells

Meuth, Mark

doi:10.1016/0304-419x(90)90009-p

Cited by 51 publications

(31 citation statements)

References 66 publications

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“…Treatments such as partial hepatectomy that induce cell proliferation greatly enhance the appearance of preneoplastic foci and hepatocellular carcinomas in the livers of rats treated with carcinogenic chemicals (7). The (8,9). Such random errors are thought to account for the incidence of spontaneously initiated cells in the livers and other organs of control animals.…”

Section: Role Of Cell Proliferation In Carcinogenesismentioning

confidence: 99%

Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment.

Croy¹

1993

Environ Health Perspect

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There is much interest in incorporating knowledge of biological mechanisms of carcinogenesis into assessments of health risks to humans posed by chemicals in the environment. Debate over the soundness of using data from animal bioassays conducted at minimally toxic doses or fractions thereof for predicting cancer risks to humans exposed to much lower doses has stimulated interest in the question of whether genotoxic or mitotic effects predominate in chemical carcinogenesis. Cell division plays a key role at each stage in the evolution of cancer, and it is well documented that increased rates of cell proliferation can escalate the risk of malignancy. This article examines the current understanding of both mechanisms by which chemicals provoke cell proliferation and the contribution of various kinetic patterns of cell proliferation to carcinogenesis.

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Section: Role Of Cell Proliferation In Carcinogenesismentioning

confidence: 99%

Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment.

Croy¹

1993

Environ Health Perspect

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“…Recircularization studies of a linearized SV40 genome passed through CV 1 monkey cells, and plasmid rejoining studies with Xenopus laevis egg and human cell extracts, have shown that these end-joining processes frequently use overlaps of one to six complementary bases (36,44,48). The products of illegitimate recombination between segments of mammalian chromosomes have been studied by examination of translocation breakpoints and deletion and insertion junctions at various genetic loci (24,25 bination, the initial steps leading to the recombinational event and the mechanisms involved are not understood.To study the products of illegitimate recombination induced by DNA double-strand breaks in a mammalian chromosome, we chose to examine the mutations that restriction enzymes induce in the endogenous adenine phosphoribosyltransferase (APRT) gene when introduced into cultured Chinese hamster ovary (CHO) cells. Restriction enzymes recognize, bind to, and cleave specific DNA sequences to produce DNA double-strand breaks (27,38).…”

mentioning

confidence: 99%

“…DNA double-strand breaks can cause chromosomal rearrangements (1), which can lead to cell killing (13), mutagenesis (25), and cell transformation (5). To understand how DNA double-strand breaks lead to genetic rearrangements, it is important to understand the mechanisms of DNA double-strand-break rejoining and how these processes are carried out at the DNA and chromosomal levels.…”

mentioning

confidence: 99%

“…Recircularization studies of a linearized SV40 genome passed through CV 1 monkey cells, and plasmid rejoining studies with Xenopus laevis egg and human cell extracts, have shown that these end-joining processes frequently use overlaps of one to six complementary bases (36,44,48). The products of illegitimate recombination between segments of mammalian chromosomes have been studied by examination of translocation breakpoints and deletion and insertion junctions at various genetic loci (24,25). Although many of the breakpoint junctions show the small complementary base overlaps that are the signature of illegitimate recom-bination, the initial steps leading to the recombinational event and the mechanisms involved are not understood.…”

mentioning

confidence: 99%

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Illegitimate recombination induced by DNA double-strand breaks in a mammalian chromosome.

Phillips¹,

Morgan²

1994

Mol. Cell. Biol.

110

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We examined DNA double-strand-break-induced mutations in the endogenous adenine phosphoribosyltransferase (APRT) gene in cultured Chinese hamster ovary cells after exposure to restriction endonucleases. PvuII, EcoRV, and StuI, all of which produce blunt-end DNA double-strand breaks, were electroporated into CHO-AT3-2 cells hemizygous at the APRT locus. Colonies of viable cells containing mutations at APRT were expanded, and the mutations that occurred during break repair were analyzed at the DNA sequence level. Restriction enzyme-induced mutations consisted of small deletions of 1 to 36 bp, insertions, and combinations of insertions and deletions at the cleavage sites. Most of the small deletions involved overlaps of one to four complementary bases at the recombination junctions. Southern blot analysis revealed more complex mutations, suggesting translocation, inversion, or insertion of larger chromosomal fragments. These results indicate that blunt-end DNA double-strand breaks can induce illegitimate (nonhomologous) recombination in mammalian chromosomes and that they play an important role in mutagenesis.In the mammalian genome, DNA double-strand breaks can occur during cellular processes (4,46) or as the result of exposure to DNA-damaging agents (51). DNA double-strand breaks can cause chromosomal rearrangements (1), which can lead to cell killing (13), mutagenesis (25), and cell transformation (5). To understand how DNA double-strand breaks lead to genetic rearrangements, it is important to understand the mechanisms of DNA double-strand-break rejoining and how these processes are carried out at the DNA and chromosomal levels.Studies of plasmid integration in a variety of mammalian cell types, along with simian virus 40 (SV40) recircularization studies with monkey cells, have shown that mammalian cells predominantly repair DNA double-strand breaks by endjoining mechanisms that do not require extensive homology between the molecules to be joined (39). Recombination between nonhomologous DNA substrates was first described for bacteria (15) and has been defined as illegitimate recombination (16). Most studies examining illegitimate recombination have used DNA substrates linearized with various restriction endonucleases to produce specific combinations of end structures. These substrates are cleaved in vitro and passed through various cellular and cell-free systems, and the rejoined products are studied. Recircularization studies of a linearized SV40 genome passed through CV 1 monkey cells, and plasmid rejoining studies with Xenopus laevis egg and human cell extracts, have shown that these end-joining processes frequently use overlaps of one to six complementary bases (36,44,48). The products of illegitimate recombination between segments of mammalian chromosomes have been studied by examination of translocation breakpoints and deletion and insertion junctions at various genetic loci (24,25 bination, the initial steps leading to the recombinational event and the mechanisms involved are not understood.To study the...

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“…In recent years, technical advances have provided efficient methods for molecular analysis of mutations in defined target genes (61). The polymerase chain reaction (PCR), DNA sequence analysis, and the isolation ofmolecular probes to various loci have been used to efficiently recover and identify mutations.…”

Section: The Futurementioning

confidence: 99%

Fertility, reproduction, and genetic disease: studies on the mutagenic effects of environmental agents on mammalian germ cells.

Shelby

Bishop

Mason

et al. 1993

Environ Health Perspect

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Because geneticaly based diseases have a major inpact on human health, the National Institute of Environmental Health Sciences (NIEHS) has conducted a research and testing program for more than a decade to address chemical induction of heritable genetic damage in the germ cells of mammals. Although most genetic disease results from preexisting mutations, a portion is due to the occurrence ofnew mutations. The supposition that exposure to mutagenic c s contributes to the occurrence of new mutations in the human population is strongly supported by the results from animal models. Such studies clearly demonstrate the potential ofemnironmental chemicals to induce mutations in both somatic and reproductive cells of mammals. This NIEHS program has become a leader in the identification ofgenetic hazards in the environment and in the acquisition of animal model data used by regulatory agencies in assessing genetic risks to human health.

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The structure of mutation in mammalian cells

Cited by 51 publications

References 66 publications

Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment.

Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment.

Illegitimate recombination induced by DNA double-strand breaks in a mammalian chromosome.

Fertility, reproduction, and genetic disease: studies on the mutagenic effects of environmental agents on mammalian germ cells.

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