Burnouf D, Koehl P, Fuchs R P
Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, Strasbourg, France.
Proc Natl Acad Sci U S A. 1989 Jun;86(11):4147-51. doi: 10.1073/pnas.86.11.4147.
2-Acetylaminofluorene (AAF), a potent rat liver carcinogen that binds covalently to the C-8 position of guanine residues in DNA, is an effective frameshift mutagen. The mutations are distributed nonrandomly, in that most are located at a few specific DNA sequences (i.e., mutation hot spots). Among these hot spots, the Nar I sequence (GGCGCC) is especially susceptible to the induction of -2 frameshift mutations (GGCGCC----GGCC). Due to the nature of the Nar I sequence, G1G2CG3CC, three different molecular events, each involving the deletion of two contiguous base pairs (i.e., G2C, CG3, G3C), can give rise to the observed end point (GGCC). To compare the potential role of each of the three possible guanine-AAF adducts in the Nar I site to induce the -2 frameshift mutation, we constructed double-stranded plasmid molecules containing a single-AAF adduct bound to one of the three guanine positions. Using these plasmids, we found that only the adduct in the G3 position induces the -2 frameshift mutation. This strong effect of the position of the -AAF adduct within the Nar I site is discussed in relation to the possible involvement of an unusual DNA conformation in the mutagenic processing.
2-乙酰氨基芴（AAF）是一种强效的大鼠肝脏致癌物，它能与DNA中鸟嘌呤残基的C-8位共价结合，是一种有效的移码诱变剂。这些突变并非随机分布，因为大多数位于少数特定的DNA序列（即突变热点）。在这些热点中，Nar I序列（GGCGCC）特别容易被诱导产生-2移码突变（GGCGCC----GGCC）。由于Nar I序列G1G2CG3CC的性质，三种不同的分子事件，每种都涉及相邻两个碱基对的缺失（即G2C、CG3、G3C），都可能导致观察到的终点（GGCC）。为了比较Nar I位点上三种可能的鸟嘌呤-AAF加合物各自在诱导-2移码突变中的潜在作用，我们构建了双链质粒分子，其中单个AAF加合物与三个鸟嘌呤位置之一结合。使用这些质粒，我们发现只有G3位置的加合物能诱导-2移码突变。结合诱变过程中异常DNA构象的可能参与，讨论了Nar I位点内-AAF加合物位置的这种强烈影响。
