Human MutS alpha specifically binds to DNA containing aminofluorene and acetylaminofluorene adducts
Human MutS alpha specifically binds to DNA containing aminofluorene and acetylaminofluorene adducts
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DOI：
10.1074/jbc.271.39.24084
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发表时间：
1996-09-27
影响因子：
4.8
通讯作者：
Romano, LJ
中科院分区：
文献类型：
--
作者：
Li, GM;Wang, HX;Romano, LJ
错配修复缺陷与几种类型的癌症有关。人们还普遍认为，环境致癌物通过诱导关键基因突变而引发癌症。先前的遗传学研究表明，错配修复系统还可以识别某些形式的DNA损伤，例如O-6-甲基鸟嘌呤和紫外线光产物，因此，错配修复可能在环境因素诱发的致癌作用中发挥作用。为了检验这一假设，测试了 hMutS α（一种由 hMSH2 和 GTBP 组成并参与链特异性错配修复的异二聚体）识别含有氨基芴 (AF) 或 N-乙酰基-2-氨基芴 (AAF) 位点特异性 C-8-鸟嘌呤加合物的 DNA 的能力。我们在此表明 hMutS α 特异性结合 AF 和 AAF 加合物。这种结合需要 hMSH2 和 GTBP。竞争和滴定实验的结果表明，hMutS α 与 AF 和 AAF 的结合效率约为 G-T 错配的结合效率的 60%，但至少是与未经化学修饰的其他相同同源双链 DNA 的结合效率的 10 倍。 hMutS α 与 AF 和 AAF 加合物的特异性结合表明，链特异性错配修复参与了环境致癌物诱导的 DNA 损伤的处理。
Defects in mismatch repair are associated with several types of cancer. It is also generally believed that environmental carcinogens are responsible for the initiation of cancers by the induction of mutations in critical genes. Prior genetic studies have suggested that the mismatch repair system can also recognize certain forms of DNA damage such as O-6-methylguanine and UV photoproducts, and, therefore, mismatch repair may play a role in environmental agent-induced carcinogenesis. To examine this hypothesis, hMutS alpha, a heterodimer which consists of hMSH2 and GTBP and participates in strand specific mismatch repair, was tested for its ability to recognize DNA containing a site specific C-8-guanine adduct of aminofluorene (AF) or N-acetyl-2-aminofluorene (AAF). We show here that hMutS alpha specifically binds to both AF and AAF adducts. This binding requires both hMSH2 and GTBP. Results from competition and titration experiments indicate that the binding efficiency of hMutS alpha to AF and AAF is about 60% of that to a G-T mismatch, but is at least 10-fold that to an otherwise identical homoduplex DNA without the chemical modification. The specific binding of AF and AAF adducts by hMutS alpha suggests that strand-specific mismatch repair is involved in processing DNA damage induced by environmental carcinogens.