Department of Chemistry, The University of Chicago, 929 E. 57th Street, Chicago, IL 60637, USA.
Nucleic Acids Res. 2010 Jul;38(13):4415-25. doi: 10.1093/nar/gkq129. Epub 2010 Mar 11.
N(1)-meA and N(3)-meC are cytotoxic DNA base methylation lesions that can accumulate in the genomes of various organisms in the presence of S(N)2 type methylating agents. We report here the structural characterization of these base lesions in duplex DNA using a cross-linked protein-DNA crystallization system. The crystal structure of N(1)-meA:T pair shows an unambiguous Hoogsteen base pair with a syn conformation adopted by N(1)-meA, which exhibits significant changes in the opening, roll and twist angles as compared to the normal A:T base pair. Unlike N(1)-meA, N(3)-meC does not establish any interaction with the opposite G, but remains partially intrahelical. Also, structurally characterized is the N(6)-meA base modification that forms a normal base pair with the opposite T in duplex DNA. Structural characterization of these base methylation modifications provides molecular level information on how they affect the overall structure of duplex DNA. In addition, the base pairs containing N(1)-meA or N(3)-meC do not share any specific characteristic properties except that both lesions create thermodynamically unstable regions in a duplex DNA, a property that may be explored by the repair proteins to locate these lesions.
N(1)-meA 和 N(3)-meC 是细胞毒性 DNA 碱基甲基化损伤，在 S(N)2 型甲基化试剂存在的情况下，可以在各种生物体的基因组中积累。我们在此报告了使用交联蛋白-DNA 结晶系统在双链 DNA 中这些碱基损伤的结构特征。N(1)-meA:T 对的晶体结构显示出明确的 Hoogsteen 碱基对，其中 N(1)-meA 采用顺式构象，与正常的 A:T 碱基对相比，其开口、滚动和扭转角度有显著变化。与 N(1)-meA 不同，N(3)-meC 与相反的 G 不建立任何相互作用，但仍部分在螺旋内。同样，结构表征的是 N(6)-meA 碱基修饰，它与双链 DNA 中的相反 T 形成正常碱基对。这些碱基甲基化修饰的结构特征提供了它们如何影响双链 DNA 整体结构的分子水平信息。此外，含有 N(1)-meA 或 N(3)-meC 的碱基对除了两者都在双链 DNA 中形成热力学不稳定区域之外，没有任何特定的特征性质，这种性质可能被修复蛋白用来定位这些损伤。
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