寻找突变热点。
In search of a mutational hotspot.
作者信息
Hatahet Z, Zhou M, Reha-Krantz L J, Morrical S W, Wallace S S
机构信息
Department of Microbiology and Molecular Genetics and the Markey Center for Molecular Genetics, University of Vermont, Burlington, VT 05405, USA.
出版信息
Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8556-61. doi: 10.1073/pnas.95.15.8556.
Abstract
In vitro selection was used to define sequence contexts that significantly enhanced the mutagenic potential of 7, 8-dihydro-8-oxoguanine (8-oxoG). Contexts that simultaneously reduced the efficiency of 8-oxoG cleavage by formamidopyrimidine DNA N-glycosylase and increased the efficiency of misincorporating A opposite the lesion by DNA polymerase were isolated from a pool of 4(8) random octanucleotide sequences. Kinetic analysis showed that the combined effects of poor repair and high miscoding resulted in 10(2)- to 10(3)-fold increase in the mutagenic potential of 8-oxoG. Furthermore, the isolated sequence contexts correlated strongly with G --> T transversion hotspots in spontaneous mutational spectra reported for the Escherichia coli lacI and human p53 and factor IX genes. We present an example directly linking the interplay between DNA repair and replication to a "high risk sequence" for base substitution.
摘要
体外筛选用于确定能显著增强7,8-二氢-8-氧代鸟嘌呤（8-氧代鸟嘌呤，8-oxoG）诱变潜力的序列背景。从一组4(8)个随机八核苷酸序列中分离出了这样的序列背景，它们既能同时降低甲酰胺嘧啶DNA N-糖基化酶对8-氧代鸟嘌呤的切割效率，又能提高DNA聚合酶在损伤位点对面错误掺入腺嘌呤的效率。动力学分析表明，修复不佳和错配编码率高的综合作用导致8-氧代鸟嘌呤的诱变潜力增加了10²至10³倍。此外，分离出的序列背景与大肠杆菌lacI、人类p53和因子IX基因自发突变谱中报道的G→T颠换热点密切相关。我们给出了一个将DNA修复与复制之间的相互作用直接与碱基置换的“高风险序列”联系起来的例子。
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