Differential Nucleotide Excision Repair Susceptibility of Bulky DNA Adducts in Different Sequence Contexts: Hierarchies of Recognition Signals
Differential Nucleotide Excision Repair Susceptibility of Bulky DNA Adducts in Different Sequence Contexts: Hierarchies of Recognition Signals
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DOI：
10.1016/j.jmb.2008.09.087
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发表时间：
2009-01-09
影响因子：
5.6
通讯作者：
Broyde, Suse
中科院分区：
文献类型：
--
作者：
Cai, Yuqin;Patel, Dinshaw J.;Broyde, Suse
大体积DNA损伤的差异核苷酸切除修复（NER）敏感性的结构起源仍然是一个具有挑战性的问题。我们研究了双链DNA中的10S(+)-反式-抗-[BP]- n -2-2'-脱氧鸟苷（G*）加合物。这种加合物是由苯并[a]芘（BP）的主要遗传毒性代谢物（+）(7R,8S,9S,10R)-7,8-二羟基-9,10-环氧-7,8,9,10-四氢苯并[a]芘与鸟嘌呤的外环氨基反应而产生的。研究发现，在无细胞萃取物中，NER设备对这种病变的去除取决于病变所处的碱基序列背景，这为阐明有利于NER的受损DNA双链的特性提供了极好的机会。虽然BP环系统位于B-DNA小槽中，沿着修饰链的5'方向，但存在序列依赖的取向差异，并由侧翼氨基控制[核酸研究，35(2007),1555-1568]。为了阐明序列调控的NER敏感性，我们对5′中心点中心点CG*GC中心点中心点、5′中心点CGG*C中心点中心点、5′中心点TCG*CT中心点中心点和5′中心点TCG*CT中心点中心点含加合物双链进行了分子动力学模拟。我们还研究了含有“I”（2'-脱氧鸟苷）的5'-中心点中心点CG*TC中心点中心点和5'-中心点中心点CIG*C中心点中心点中心点，并用氢取代了2'-脱氧鸟苷中的氨基，进一步表征了侧翼氨基在受损双链中的结构和动态作用。我们的研究结果明确指出了串联GG序列中氨基对NER效率的明确作用，并提出了一系列不稳定的结构特征，这些特征在所研究的序列背景下不同程度地促进了BP病变的NER。此外，层次结构中几个局部不稳定特征的组合，与多方模型一致，可能提供相对较强的识别信号。(C) 2008 Elsevier Ltd版权所有。
The structural origin underlying differential nucleotide excision repair (NER) susceptibilities of bulky DNA lesions remains a challenging problem. We investigated the 10S (+)-trans-anti-[BP]-N-2-2'-deoxyguanosine (G*) adduct in double-stranded DNA. This adduct arises from the reaction, in vitro and in vivo, of a major genotoxic metabolite of benzo[a]pyrene (BP), (+)(7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, with the exocyclic amino group of guanine. Removal of this lesion by the NER apparatus in cell-free extracts has been found to depend on the base sequence context in which the lesion is embedded, providing an excellent opportunity for elucidating the properties of the damaged DNA duplexes that favor NER. While the BP ring system is in the B-DNA minor groove, 5' directed along the modified strand, there are orientational distinctions that are sequence dependent and are governed by flanking amino groups [Nucleic Acids Res. 35 (2007), 1555-1568]. To elucidate sequence-governed NER susceptibility, we conducted molecular dynamics simulations for the 5'-center dot center dot center dot CG*GC center dot center dot center dot, 5'-center dot center dot center dot CGG*C center dot center dot center dot, and 5'-center dot center dot center dot TCG*CT center dot center dot center dot adduct-containing duplexes. We also investigated the 5'-center dot center dot center dot CG*TC center dot center dot center dot and 5'-center dot center dot center dot CIG*C center dot center dot center dot sequences, which contain "I" (2'-deoxyinosine), with hydrogen replacing the amino group in 2'-deoxyguanosine, to further characterize the structural and dynamic roles of the flanking amino groups in the damaged duplexes. Our results pinpoint explicit roles for the amino groups in tandem GG sequences on the efficiency of NER and suggest a hierarchy of destabilizing structural features that differentially facilitate NER of the BP lesion in the sequence contexts investigated. Furthermore, combinations of several locally destabilizing features in the hierarchy, consistent with a multipartite model, may provide a relatively strong recognition signal. (C) 2008 Elsevier Ltd. All rights reserved.