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首页> 外文期刊>Biochemistry >NMR Solution Structures of Clustered Abasic Site Lesions in DNA: Structural Differences between 3'-Staggered (-3) and 5'-Staggered (+3) Bistranded Lesions
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NMR Solution Structures of Clustered Abasic Site Lesions in DNA: Structural Differences between 3'-Staggered (-3) and 5'-Staggered (+3) Bistranded Lesions

机译：DNA中成簇的基础位点病变的NMR溶液结构：3'-交错（-3）和5'-交错（+3）刚毛病变之间的结构差异

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摘要

Ionizing radiation produces a distinctive pattern of bistranded clustered lesions in DNA. A relatively low number of clustered lesions may be lethal to cells when compared to a larger number of single lesions. Enzyme cleavage experiments suggest that the orientation of bistranded lesions causes differential recognition and removal of these lesions. Like that of a previous study of bistranded abasic site lesion [Hazel, R. D., Tian, K., and de los Santos, C. (2008) Biochemistry 47, 11909-11919], the aim of this investigation was to determine the structures of two DNA duplexes each containing two synthetic apurinic/apyrimidinic (AP) residues, positioned on opposite strands and separated by two base pairs. In the first duplex, the AP residues are staggered in the 3' orientation [-3 duplex. (AP)_2-3 duplex], while in the second duplex, the AP residues are staggered in the 5' orientation [+3 duplex. (AP)_2+3 duplex]. NOESY spectra recorded in 100 and 10% D_20 buffer solutions allowed the assignment of the nonexchangeable and exchangeable protons, respectively, for each duplex. Cross-peak connectivity in the nonexchangeable proton spectra indicates that the duplex is a regular right-handed helix with the AP residues and orphan bases located inside the duplexes. The exchangeable proton spectra establish the formation of Watson—Crick GC alignment for the two base pairs between the lesion sites in both duplexes. Distance-restrained molecular dynamics simulation confirmed the intrahelical orientations of the AP residues. The proximity of the AP residues across the minor groove of the —3 duplex and across the major groove in the +3 duplex is similar to their locations in the case of —1 and +1 clusters. This difference in structure may be a key factor in the differential recognition of bistranded AP lesions by human AP endonuclease.
机译：电离辐射会在DNA中产生鲜明的簇状簇状病变。与大量单个病变相比，相对较少数量的聚集性病变可能对细胞致死。酶切实验表明，双侧病变的方向引起了这些病变的区别识别和去除。就像先前对双足无基础性位病变的研究[Hazel，RD，Tian，K.，and de los Santos，C.（2008）Biochemistry 47，11909-11919]一样，本研究的目的是确定肝组织的结构。两个DNA双链体，每个双链体包含两个合成的嘌呤/嘧啶（AP）残基，位于相对链上，并被两个碱基对隔开。在第一双链体中，AP残基在3'方向[-3双链体中交错排列。 （AP）_2-3双工]，而在第二个双工中，AP残基在5'方向[+3双工]上交错排列。 （AP）_2 + 3双工]。在100和10％D_20缓冲溶液中记录的NOESY光谱分别为每个双链体分配了不可交换和可交换的质子。不可交换质子谱中的跨峰连通性表明双链体是规则的右旋螺旋，AP残基和孤儿碱基位于双链体内部。可交换的质子光谱为两个双链体病变部位之间的两个碱基对建立了Watson-Crick GC对准。距离受限的分子动力学模拟证实了AP残基的螺旋内取向。 AP残基跨-3双链体的小沟和+3双链体中的主沟的接近度与它们在-1和+1簇中的位置相似。这种结构上的差异可能是人AP核酸内切酶差异识别双足AP病变的关键因素。

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