Sequence Determinants for -2 Frameshift Mutagenesis atNarI-derived Hot Spots

Koffel-Schwartz, Nicole; Fuchs, Robert P. P.

doi:10.1006/jmbi.1995.0515

Cited by 40 publications

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“…Frameshift mutations induced by AAF adducts within both runs of Gs and NarI sites can be best explained by a slippage mechanism (20,33). We recently have shown that the NarI site belongs to a family of Ϫ2 frameshift mutation hot spots whose consensus sequence is 5Ј-GCGCX-3Ј (33).…”

Section: Discussionmentioning

confidence: 99%

“…Based on experiments with singly adducted plasmids, a two-step model for frameshift mutagenesis has been proposed (20,23,33). The first step involves incorporation of cytosine across from the dG-AAF adduct, followed by a slippage step during which the primer template forms one or two ''correct'' GC base pairs at the primer terminus (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…2). These SMI (20,21,33) extrude the adduct in a bulge containing one base for the run of Gs, or two bases for the NarI site (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

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SOS factors involved in translesion synthesis

Napolitano

Lambert

Fuchs

1997

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

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Mutations are permanent DNA sequence changes that can be induced when replication occurs on a damaged DNA template. In Escherichia coli, the process of translesion synthesis past a lesion that hinders replication requires the induction of SOS-controlled gene products, among which are those of the umuDC operon. To study translesion synthesis in vivo, we have constructed singlestranded vectors containing single 2-acetylaminof luorene adducts located within ؊1 and ؊2 frameshift mutation hot spots formed by short repetitive sequences. These adducts strongly hinder DNA replication as only 2-5% of the molecules give rise to progeny under non-SOS-induced conditions. Induction of the SOS response lead to a 10-fold increase in survival. Adducts present within repetitive sequences trigger the formation of misaligned primer͞template replication intermediates which, upon elongation, will result in the fixation of frameshift errors (mutagenic translesion synthesis). Surprisingly we find that elongation from the nonslipped intermediate depends upon functional umuDC ؉ gene products, whereas elongation from the slipped intermediate is umuDC ؉ independent but requires another, as yet biochemically uncharacterized, SOS function. These data are discussed in terms of the different steps involved during translesion synthesis through a replication-blocking lesion.Organisms have developed various strategies to protect their genomes from the damaging effects of endogenous and exogenous agents. Despite having robust excision repair systems that remove DNA lesions before replication, cells also possess efficient strategies for tolerating lesions persisting at the replication fork during DNA synthesis (1). Two basic strategies of lesion tolerance can be distinguished: (i) translesion synthesis (TLS) is a process during which the replication machinery reads through the lesion with an associated risk of fixing a mutation. If the lesion does not impede DNA synthesis, an unmodified replication complex can achieve TLS. However, a replication complex modified by accessory proteins encoded by genes associated with the SOS regulon is required for TLS of lesions that hinder the progression of replication; and (ii) damage avoidance designates a general strategy that facilitates replication of damaged DNA templates without the need for the polymerase to read through the lesion. This strategy takes advantage of the information contained in the complementary strand. Two models of damage avoidance have been proposed (1-3): (i) postreplication recombinational repair, in which the DNA polymerase, blocked at a lesion site, dissociates from the DNA and reinitiates replication downstream from the lesion, leaving a gap that is repaired by a recombination mechanism involving the sister chromatid; and (ii) polymerase strand switching, in which the DNA polymerase switches temporarily from the damaged parental template to the undamaged newly synthesized strand of the sister chromatid before returning to the parental template downstream from the lesion. B...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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SOS factors involved in translesion synthesis

Napolitano

Lambert

Fuchs

1997

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

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“…8. The role of the bases flanking the central dinucleotide GC repeat in the NarI sequence (N;,GCGCN,,) on the mutation frequency induced by N-2-acetylaminofluorene has been investigated (Koffel-Schwartz and Fuchs, 1995). The nucleotide Nb, located 3' to the central region, strongly modulates the mutation frequency while the nucleotide N,, located at the 5' side, has little effect.…”

Section: Banementioning

confidence: 99%

NMR Data Show that the Carcinogen N‐2‐Acetylaminofluorene Stabilises an Intermediate of −2 Frameshift Mutagenesis in a Region of High Mutation Frequency

Milhe

Fuchs

Lefèvre

1996

European Journal of Biochemistry

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The heteroduplex, d(ACCGGCGCCACA) . d(TGTGG-CCGGT), containing two bulged bases, a cytosine and the guanine G7, either unmodified or modified with the carcinogen N-2-acetylaminofluorene, have been studied by NMR as models of slipped-mutagenic intermediates (SMI). The melting temperature of the modified heteroduplex is strongly increased compared with that of the unmodified heteroduplex. NMR studies have shown that all the bases of the unmodified heteroduplex are stacked within the helix, without any disruption of the sequential connectivities. The two strands are in a B-like conformation. Nevertheless, exchangeable-proton studies have revealed that base pairing is very weak, or even lacking, over two base pairs apart from the bulge. Concerning the modified heteroduplex, no B-like connectivity is observed in the G5-C9 segment. Moreover, the cytosine C8 is rejected outside the helix, whereas the N-2-acetylaminofluorene moiety is inserted within the helix. The G5 . C18, C6 . G17 and C9 . GI6 bases are remarkably stable when the temperature is increased, in agreement with the high melting temperature. Some small unassigned peaks reveal the presence of the minor conformation in equilibrium. The strong stabilisation of the N-2-acetylaminofluorene-modified heteroduplex compared with the unmodified duplex is in agreement with the high N-2-acetylaminofluorene-induced mutation frequency compared with the spontaneous frequency and with the hypothesis of mutagenesis occurring during replication.

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“…Thus, although misalignment is potentially mutagenic, it might assist the DNA polymerase in overcoming replication blocks by stabilization of bypass intermediates. The importance of DNA misalignment mechanisms in lesion bypass was previously reported for a number of DNA polymerases (28)(29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 65%

Lesion bypass DNA polymerases replicate across non-DNA segments

Maor-Shoshani

Ben-Ari

Livneh

2003

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

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A critical feature of the robustness of the DNA replication machinery is the ability to complete its task in the presence of interfering DNA damage. A key mechanism responsible for this task is translesion replication (also termed translesion synthesis), carried out by specialized lesion bypass DNA polymerases of the Y superfamily. Here we show that in Escherichia coli, plasmids can be replicated across a segment of foreign non-DNA material, consisting of hydrocarbon chains of 3 or 12 methylene residues. This replication is carried out by DNA polymerase V and proceeds by at least two mechanisms: (i) Editing out the foreign insert, by polymerase ''hopping'' across it, which can be mediated by looping out of the insert, leading to its deletion, while preserving the DNA sequence.(ii) DNA synthesis through the insert, which occurs by incorporating one or two nucleotides opposite the hydrocarbon chain, yielding a net increase in the length of the DNA sequence. The remarkable ability of DNA polymerase V to insert nucleotides opposite a hydrocarbon chain shows that DNA synthesis can occur in a region of the template strand, which lacks all fundamental features of DNA, including its purine, pyrimidine, sugar, and phosphate moieties, and its hydrophilic and ionic nature. This bypass ability reflects a striking robustness of the translesion replication apparatus and is likely to contribute to its effectiveness in maintaining genome stability.

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Sequence Determinants for -2 Frameshift Mutagenesis atNarI-derived Hot Spots

Cited by 40 publications

References 0 publications

SOS factors involved in translesion synthesis

SOS factors involved in translesion synthesis

NMR Data Show that the Carcinogen N‐2‐Acetylaminofluorene Stabilises an Intermediate of −2 Frameshift Mutagenesis in a Region of High Mutation Frequency

Lesion bypass DNA polymerases replicate across non-DNA segments

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