DNA sequence determination of γ-radiation-induced mutations of the hamster aprt locus

Miles, Carol; Meuth, Mark

doi:10.1016/0165-7992(89)90004-3

Cited by 57 publications

(26 citation statements)

References 23 publications

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“…2A). The microdeletion, comparable in size to other radiation-induced lesions (Grosovsky et al, 1988;Miles and Meuth, 1989), was absent in the parental strains and co-segregated invariably with the mutant phenotype (Fig. 2B).…”

Section: Chromosomal Localization Of the Pcm Locusmentioning

confidence: 90%

Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice

et al. 2004

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an erythropoietin (Epo)-dependent polycythemia in heterozygotes and a hypochromic, microcytic anemia in homozygotes. Interestingly, both defects in erythropoiesis were transient, correcting by young adulthood. Delayed upregulation of the negative hormonal regulator of iron homeostasis, hepcidin (Hamp), during postnatal development correlates strongly with profound increases in Fpn1 protein levels and polycythemia in Pcm heterozygotes. Thus, our data suggest that a Hampmediated regulatory interference alleviates the defects in iron homeostasis and transient alterations in erythropoiesis caused by a regulatory mutation in Fpn1.

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Section: Chromosomal Localization Of the Pcm Locusmentioning

confidence: 90%

Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice

et al. 2004

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“…We first asked whether, as in other systems, nonsense mutations in this gene decrease aprt mRNA levels. We obtained from Mark Meuth a set of mutant CHO cell lines carrying nonsense mutations in several different exons of the aprt gene (44,49). The names of these mutants and the locations of the mutations are presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To study the effect of nonsense mutation in the aprt gene, we obtained from Mark Meuth, University of Utah, a set of CHO cell lines (S1, S20, S23, S62, S69, XA50, and XA52) carrying nonsense mutations in either exon 1, 2, 4, or 5 of the aprt gene (44,49). As a wild-type standard, we used the parental hemizygous cell line CHO D422, which bears a single copy of the aprt gene (9).…”

Section: Methodsmentioning

confidence: 99%

Effects of Nonsense Mutations on Nuclear and Cytoplasmic Adenine Phosphoribosyltransferase RNA

Kessler

Chasin

1996

Molecular and Cellular Biology

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We have analyzed Chinese hamster ovary (CHO) cell mutants bearing nonsense codons in four of the five exons of the adenine phosphoribosyltransferase (aprt) gene and have found a pattern of mRNA reduction similar to that seen in systems studied previously: a decrease in steady-state mRNA levels of 5-to 10-fold for mutations in exons 1, 2, and 4 but little effect for mutations in the 3-most exon (exon 5). Nuclear aprt mRNA levels showed a similar decrease. Nonsense-containing aprt mRNA decayed at the same rate as wild-type mRNA in these cell lines after inhibition of transcription with actinomycin D. Nonsense-containing aprt mRNA is associated with polysomes, ruling out a model in which stable residual mRNA escapes degradation by avoiding translation initiation. A tetracycline-responsive form of the aprt gene was used to compare the stability of nonsense-containing and wild-type aprt mRNAs without globally inhibiting transcription. In contrast to measurements made in the presence of actinomycin D, after inhibition of aprt transcription with tetracycline, a nonsense-mediated destabilization of aprt mRNA was indeed demonstrable. The increased rate of decay of cytoplasmic aprt mRNA seen here could account for the nonsense-mediated reduction in steady-state levels of aprt mRNA. However, the low levels of nonsense-bearing aprt mRNA in the nucleus suggest a sensibility of mRNA to translation or translatability before it exits that compartment. Quantitation of the steady-state levels of transcripts containing introns revealed no accumulation of partially spliced aprt RNA and hence no indication of nonsense-mediated aberrancies in splicing. Our results are consistent with a model in which translation facilitates the export of mRNA through a nuclear pore. However, the mechanism of this intriguing nucleocytoplasmic communication remains to be determined.Mutations that introduce premature translation termination codons into the protein-coding region of genes result more often than not in decreased steady-state levels of the corresponding mRNA. This nonsense mutation-mediated mRNA reduction has been found wherever sought among living organisms, in bacteria (47), yeasts (37), plants (60), and humans (17,58). This phenomenon in yeasts has been termed nonsense-mediated mRNA decay, because it is clear that the stability of mature mRNA is affected (28,35). Extensive sitedirected mutagenesis studies of yeasts have identified sequences within the mRNA that are necessary to trigger accelerated mRNA decay (28,48,63,64). The isolation of mutants resistant to general nonsense-mediated mRNA reduction has led to the identification of several genes required for this phenomenon: upf genes in Saccharomyces cerevisiae (16,35) and smg genes in Caenorhabditis elegans (50). Genetic analysis of yeast cells has also suggested that the process of nonsensemediated mRNA degradation differs in at least some steps from that of normal mRNA degradation (45). However, the molecular mechanism involved in this cytoplasmic decay has yet to be fully elucidate...

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“…Tandem mutations are rare among spontaneous events analyzed in other systems, accounting for -1% of mutations at the aprt locus of CHO cells (29) and 1 to 2% of mutations of integrated shuttle vector-borne targets in mouse cells (1,18). These mutations can be induced by DNA-damaging agents, such as UV (8,32) or y radiation (24). Thus, spontaneous lesions similar to those induced by these agents might conceivably lead to the tandem mutations found in SW620.…”

Section: Discussionmentioning

confidence: 99%

Multiple dispersed spontaneous mutations: a novel pathway of mutation in a malignant human cell line.

Harwood¹,

Tachibana²,

Meuth³

1991

Mol. Cell. Biol.

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We analyzed the nature of spontaneous mutations at the autosomal locus coding for adenine phosphoribosyltransferase in the human colorectal carcinoma cell line SW620 to establish whether distinctive mutational pathways exist that might underlie the more complex genome rearrangements arising in tumor cells. Point mutations occur at a low rate in aprt hemizygotes derived from SW620, largely as a result of base substitutions at G-C base pairs to yield transversions and transitions. However, a novel pathway is evident in the form of multiple dispersed mutations in which two errors, separated by as much as 1,800 bp, fall in the same mutant gene. Such mutations could be the result of error-prone DNA synthesis occurring during normal replication or during long-patch excision-repair of spontaneously arising DNA lesions. This process could also contribute to the chromosomal instability evident in these tumor cells.

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DNA sequence determination of γ-radiation-induced mutations of the hamster aprt locus

Cited by 57 publications

References 23 publications

Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice

Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice

Effects of Nonsense Mutations on Nuclear and Cytoplasmic Adenine Phosphoribosyltransferase RNA

Multiple dispersed spontaneous mutations: a novel pathway of mutation in a malignant human cell line.

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