CARCINOGEN-INDUCED FRAMESHIFT MUTAGENESIS IN REPETITIVE SEQUENCES
CARCINOGEN-INDUCED FRAMESHIFT MUTAGENESIS IN REPETITIVE SEQUENCES
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DOI：
10.1073/pnas.89.4.1310
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发表时间：
1992-02-15
影响因子：
11.1
通讯作者：
FUCHS, RPP
中科院分区：
文献类型：
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作者：
LAMBERT, IB;NAPOLITANO, RL;FUCHS, RPP
我们已经构建了质粒pS 3G-1和pSG 4，它们分别在三个（5 ′-CCCG 1G 2G 3 - 3 ′）和四个（5 ′-CG 1GGG 4 T-3 ′）鸟嘌呤残基的连续运行中含有单个乙酰氨基芴加合物。在大肠杆菌中，诱导-1移码突变的频率强烈依赖于修饰的位置：pS 3G-G3的致突变性分别几乎等于pS 3G-G1和pS 3G-G2的100倍和10倍; pSG 4-G4的致突变性几乎等于pSG 4-G1的600倍。突变是SOS依赖性的，并显着减少在细菌中，是精通核苷酸切除修复相比，修复缺陷uvrA 6突变体。DNA测序显示，pS 3G-1中的-1移码事件由鸟嘌呤序列内的靶向突变（> 90%的诱导突变）或5'侧翼重复胞嘧啶序列中的靶向突变（< 10%）组成。当乙酰氨基芴修饰在G1和G2时观察到的半靶向事件表明，损伤可以降低模板链上其位置的5'位置处的复制保真度。在质粒pSG 4中没有观察到加合物的5'端缺少重复序列的移码。我们的结果与移码突变的模型一致，其中乙酰氨基芴加合物（i）允许在DNA合成期间与大体积损伤相对的胞嘧啶准确掺入，以及（ii）阻碍与模板链上的加合物相对或5'形成的引物/模板末端的延伸，从而增加了形成滑动移码中间体的机会。
We have constructed plasmids pS3G-1 and pSG4 that contain single acetylaminofluorene adducts within contiguous runs of three (5'-CCCG1G2G3-3') and four (5'-CG1GGG4T-3') guanine residues, respectively. In Escherichia coli, the frequency of induced -1 frameshift mutations was strongly dependent on the position of modification: pS3G-G3 was almost-equal-to 100-fold and 10-fold more mutagenic than pS3G-G1 and pS3G-G2, respectively; pSG4-G4 was almost-equal-to 600-fold more mutagenic than pSG4-G1. Mutagenesis was SOS-dependent and was markedly reduced in bacteria that were proficient in nucleotide excision repair as compared to a repair-deficient uvrA6 mutant. DNA sequencing showed that -1 frameshift events in pS3G-1 consisted of either targeted mutations (> 90% of induced mutations) within the guanine sequence or semitargeted mutations (< 10%) in the 5' flanking repetitive cytosine sequence. Semitargeted events, which were observed when acetylaminofluorene modification was at G1 and G2, Show that a lesion can reduce the fidelity of replication at positions 5' to its location on the template strand. No semitargeted frameshifts were observed in plasmid pSG4, which lacks a repetitive sequence 5' to the adduct. Our results are consistent with a model for frameshift mutagenesis in which the acetylaminofluorene adduct (i) allows accurate incorporation of cytosine opposite the bulky lesion during DNA synthesis and (ii) impedes elongation of primer/template termini formed opposite the adduct or 5' to the adduct on the template strand, providing increased opportunity for the formation of slipped frameshift intermediates.