Frameshift Mutation: Determinants of Specificity

Ripley, Lynn S.

doi:10.1146/annurev.ge.24.120190.001201

Cited by 235 publications

(91 citation statements)

References 48 publications

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“…Misaligned p/t DNA structures have been proposed to account for slippage mispairing events leading to frameshift and base substitution mutations for normal (52)(53)(54) and damaged DNA (55). In the standard misalignment model (Fig.…”

Section: ϫ6mentioning

confidence: 99%

“…8, target loop-out). This correctly inserted dGMP can then either be extended, resulting in a Ϫ1 frameshift error, or template realignment can occur, relocating dGMP opposite G and resulting in a base substitution (52)(53)(54). Such dNTP-stabilized misalignment is most likely to result in a frameshift mutation, but base substitutions can also occur (34).…”

Section: ϫ6mentioning

confidence: 99%

“…dGMP or dTMP might be misincorporated directly opposite the target G and primer slippage might then align the mismatched terminal nucleotide opposite the matched downstream template base via a standard misalignment mechanism (52)(53)(54). In this scenario, misalignment would occur after rather than before the misincorporation event and the misaligned structure might be sufficiently stable to inhibit proofreading.…”

Section: ϫ6mentioning

confidence: 99%

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Fidelity of Escherichia coli DNA Polymerase III Holoenzyme

Bloom

Chen

Fygenson

et al. 1997

Journal of Biological Chemistry

116

103

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The fidelity of Escherichia coli DNA polymerase III (pol III) is measured and the effects of ␤, ␥ processivity and ⑀ proofreading subunits are evaluated using a gel kinetic assay. Pol III holoenzyme synthesizes DNA with extremely high fidelity, misincorporating dTMP, dAMP, and dGMP opposite a template G target with efficiencies f inc ‫؍‬ 5.6 ؋ 10 ؊6 , 4.2 ؋ 10 ؊7, and 7 ؋ 10 ؊7 , respectively. Elevated dGMP⅐G and dTMP⅐G misincorporation efficiencies of 3.2 ؋ 10 ؊5 and 5.8 ؋ 10 ؊4, attributed to a "dNTP-stabilized" DNA misalignment mechanism, occur when C and A, respectively, are located one base downstream from the template target G. At least 92% of misinserted nucleotides are excised by pol III holoenzyme in the absence of a next correct "rescue" nucleotide. As rescue dNTP concentrations are increased, pol III holoenzyme suffers a maximum 8-fold reduction in fidelity as proofreading of mispaired primer termini are reduced in competition with incorporation of a next correct nucleotide. Compared with pol III holoenzyme, the ␣ holoenzyme, which cannot proofread, has 47-, 32-, and 13-fold higher misincorporation rates for dGMP⅐G, dTMP⅐G, and dAMP⅐G mispairs. The first in vitro measurement of DNA synthesis fidelity was carried out by Kornberg and co-workers in 1962 (1) to analyze the mutagenic behavior of 5-bromouracil. Pol I 1 was found to misincorporate dGMP more readily opposite template bromouracil than opposite T, thus providing a biochemical basis for understanding bromouracil's ability to stimulate A⅐T 3 G⅐C transition mutations in Escherichia coli and bacteriophage T4 (2, 3). The next 3 decades bore witness to a wide range of fidelity studies investigating the biochemical basis of spontaneous and base analog-induced mutagenesis. These studies focused primarily on elucidating the properties of DNA polymerases and proofreading 3Ј-exonucleases and on developing and implementing methods to measure in vitro and in vivo mutational spectra. A comprehensive review of the first 30 years of fidelity studies is contained in Refs. 4 and 5. DNA polymerases by themselves synthesize DNA with relatively low processivity. However, polymerases can interact with groups of accessory proteins to carry out processive chromosomal replication. The first experiments to identify and characterize proteins that confer high processivity were performed by Alberts, Nossal, and co-workers (6, 7) using T4 bacteriophage. These studies were instrumental for the subsequent development of in vitro systems to study replication holoenzymes from E. coli (8 -10), T7 bacteriophage (11), and eucaryotes (12, 13).E. coli ␤ subunit is required to allow pol III core to attain high processivity (8,14). X-ray diffraction data show that the ␤ subunit is a doughnut-shaped dimer that can form a ring around DNA (15) and functions as a sliding clamp that inhibits dissociation of pol III core from DNA during chain elongation (14). The five-subunit ␥ complex is required to load ␤ onto DNA (9, 10). The processivity of pol III core alone is only 10 -20 nucleotides...

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Section: ϫ6mentioning

confidence: 99%

Section: ϫ6mentioning

confidence: 99%

Section: ϫ6mentioning

confidence: 99%

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Fidelity of Escherichia coli DNA Polymerase III Holoenzyme

Bloom

Chen

Fygenson

et al. 1997

Journal of Biological Chemistry

116

103

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“…Single base deletions in mononucleotide repeats are characteristic of polymerase errors (Ripley, 1990) and are believed to occur by a template-slippage mechanism.…”

Section: A Dna Polymerasementioning

confidence: 99%

Molecular handles on adaptive mutation

Rosenberg

Harris

Torkelson

1995

Molecular Microbiology

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SummaryIn one experimental system, several handles on the molecular mechanism of apparent adaptive mutation have emerged. The system is reversion of a lac frameshift mutation in Escherichia coil The molecular handles include a requirement for homologous recombination; the implication of DNA double-strand breaks as a molecular intermediate; a unique sequence spectrum of -1 deletions in mononucleotide repeats which implies polymerase errors, and also implies a failure of postsynthesis mismatch repair on those errors; and the involvement of sexual functions at some stage of the process. These molecular handles are revealing an unexpected new mechanism of mutagenesis.

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“…Deletions in simple repeats are characteristic of DNA polymerase errors (11), thought to be caused by a template slippage mechanism (12). Growth-dependent mutations might be different (i) because different polymerases with different mistake potentials could be responsible for each (9,13).…”

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confidence: 99%

Adaptive mutation sequences reproduced by mismatch repair deficiency.

Longerich

Galloway

Harris

et al. 1995

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

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Adaptive reversions of a lac frameshift mutation in Escherichia coli are -1 deletions in small mononucleotide repeats, whereas growth-dependent reversions are heterogeneous. The adaptive mutations resemble instability of simple repeats, which, in hereditary colon cancer, in yeast, and in E. coli occurs in the absence of mismatch repair. The postulate that mismatch repair is disabled transiently during adaptive mutation in E. coli is supported here by the demonstration that the growth-dependent mutation spectrum can be made indistinguishable from adaptive mutations by disallowing mismatch repair during growth. Physiologically induced mismatch repair deficiency could be an important mutagenic mechanism in cancers and in evolution.Adaptive mutations occur in the apparent absence of cell division, in cells exposed to a nonlethal selection (1-6), and have been detected only in genes whose function was selected (refs. 2, 4, .and 7, but see ref. 6). Thus, these mutations differ from spontaneous mutations in growing cells. In an experimental system that detects reversion of a + 1 frameshift mutation in an Escherichia coli lacI-lacZ fusion gene (2), the adaptive mutations are further distinguished from the growthdependent reversions by their molecular mechanism of formation and by their sequences. The adaptive reversions alone require genes of the E. coli RecBCD recombination system (8), implying that genetic recombination is part of the molecular mechanism by which they form. Also, the adaptive Lac' reversions are almost all single-base deletions in small mononucleotide repeats, whereas the growth-dependent Lac+ reversions include large and small insertions, deletions, and duplications and are not confined to simple repeats (9,10). This paper addresses the origin of the unusual sequence spectrum of the adaptive reversions of the lac +1 frameshift mutation.

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Frameshift Mutation: Determinants of Specificity

Cited by 235 publications

References 48 publications

Fidelity of Escherichia coli DNA Polymerase III Holoenzyme

Fidelity of Escherichia coli DNA Polymerase III Holoenzyme

Molecular handles on adaptive mutation

Adaptive mutation sequences reproduced by mismatch repair deficiency.

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