On the dependence of spontaneous mutation rates on the functional state of genes

Korogodin, V.I.; Korogodina, Victoria L.; Fajszi, Cs.; Chepurnoy, A. I.; Mikhova-Tsenova, N; Simonyan, N.V.

doi:10.1002/yea.320070204

Cited by 29 publications

(28 citation statements)

References 33 publications

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“…This in turn could lead to higher levels of spontaneous mutagenesis in a frequently transcribed gene because of the natural error frequency of the DNA-repair polymerase. There is indeed evidence that the rate of spontaneous mutagenesis in yeast increases when the transcription rate is increased (19). More surprises and complexities may be in store before we fully understand the mechanism and biological implications of transcription-coupled repair.…”

Section: Replication Complexmentioning

confidence: 96%

Transcription-Coupled Repair and Human Disease

Hanawalt¹

1994

Science

488

333

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Section: Replication Complexmentioning

confidence: 96%

Transcription-Coupled Repair and Human Disease

Hanawalt¹

1994

Science

488

333

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“…12), and the generation of base substitutions by the hypermutation process has been broadly correlated with the extent of transcription (5). Furthermore, mutagenesis and transcription are linked in yeast (13). DNA damage in the V region, or transcriptional stalling at pause sites, might be envisaged to initiate nucleotide excision repair events with an occasional error occurring during gap filling (6).…”

mentioning

confidence: 99%

Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2

Winter

Phung

Umar

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Mutations are introduced into rearranged Ig variable genes at a frequency of 10 ؊2 mutations per base pair by an unknown mechanism. Assuming that DNA repair pathways generate or remove mutations, the frequency and pattern of mutation will be different in variable genes from mice defective in repair. Therefore, hypermutation was studied in mice deficient for either the DNA nucleotide excision repair gene Xpa or the mismatch repair gene Pms2. High levels of mutation were found in variable genes from XPA-deficient and PMS2-deficient mice, indicating that neither nucleotide excision repair nor mismatch repair pathways generate hypermutation. However, variable genes from PMS2-deficient mice had significantly more adjacent base substitutions than genes from wild-type or XPA-deficient mice. By using a biochemical assay, we confirmed that tandem mispairs were repaired by wild-type cells but not by Pms2 ؊/؊ human or murine cells. The data indicate that tandem substitutions are produced by the hypermutation mechanism and then processed by a PMS2-dependent pathway.During somatic hypermutation of Ig variable (V) genes in B lymphocytes, a large number of nucleotide substitutions are introduced into a small area of the genome for the purpose of generating variant antibodies with high affinity for cognate antigens. Substitutions are distributed at a frequency of 10 Ϫ2 ͞bp over a 2-kilobase region of DNA that includes the rearranged V gene and noncoding flanking sequences (1-4). Transgenic mice with modified Ig genes have shown that both promoter and enhancer transcription elements are required for hypermutation, perhaps by making the region more accessible to proteins causing mutation (5-8). More than 90% of the mutations are base substitutions, and the rest are deletions and insertions (4, 9). An analysis of the substitutions shows that transitions occur more frequently than transversions, and there are fewer mutations of T than of the other three nucleotides (10). Thus, the substitutions are somewhat asymmetric on each of the two strands (11), but it is not known whether they are preferentially introduced into one strand and͞or preferentially removed from one strand. The presence of multiple mutations implies that DNA repair pathways are involved in generating or removing them. We therefore studied the role of nucleotide excision repair and mismatch repair on the frequency and pattern of hypermutation.A possible role for nucleotide excision repair in somatic hypermutation of V genes has been proposed. Nucleotide excision repair is especially efficient in actively transcribed genes (reviewed in ref. 12), and the generation of base substitutions by the hypermutation process has been broadly correlated with the extent of transcription (5). Furthermore, mutagenesis and transcription are linked in yeast (13). DNA damage in the V region, or transcriptional stalling at pause sites, might be envisaged to initiate nucleotide excision repair events with an occasional error occurring during gap filling (6). Mice lacking the xer...

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“…Davis (1989) has suggested that the transcriptional induction of speci®c genes under the starvation conditions can itself be mutagenic. Korogodin et al (1991) observed that the frequency of reversion of ade2 in yeast is related to its transcription level during residual growth after the initiation of speci®c starvation for adenine. The rate of spontaneous reversion increases when the mutant gene is highly transcribed (Datta and Jinks-Robertson 1995).…”

Section: Discussionmentioning

confidence: 99%

The involvement of the RAD6 gene in starvation-induced reverse mutation in Saccharomyces cerevisiae

Storchová

Gil²,

Janderová³

et al. 1998

Mol Gen Genet

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The accumulation of Ade+ revertants during adenine starvation and Trp+ revertants during tryptophan starvation in haploid polyauxotrophic strains of Saccharomyces cerevisiae occurs in a time-dependent manner. Accumulation of revertants is enhanced in Rad6- strains, suggesting that starvation-induced reversion is influenced by some of the RAD6 gene functions. The higher frequency of adaptive reversions in Rad6- strains is somewhat influenced by, but does not totally depend on, the genetic background. Therefore, the RAD6 gene product is involved in maintaining a low level not only of spontaneous mutation but also of starvation-induced reversion. The starvation-induced Ade+ and Trp+ reversions both appear to be adaptive. The analysis of growth characteristics and the genotype of revertants shows a difference between early and late-appearing revertants. These results support the hypothesis that the adaptivity of starvation-induced reversion is based on the selective fixation of random mutations, and particularly on transcription-enhanced repair and/or mutagenesis processes.

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On the dependence of spontaneous mutation rates on the functional state of genes

Cited by 29 publications

References 33 publications

Transcription-Coupled Repair and Human Disease

Transcription-Coupled Repair and Human Disease

Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2

The involvement of the RAD6 gene in starvation-induced reverse mutation in Saccharomyces cerevisiae

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