Variable impact of conformationally distinct DNA lesions on nucleosome structure and dynamics: Implications for nucleotide excision repair.,DNA Repair

当前位置： X-MOL 学术 › DNA Repair › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Variable impact of conformationally distinct DNA lesions on nucleosome structure and dynamics: Implications for nucleotide excision repair.
DNA Repair ( IF 3.0 ) Pub Date : 2019-12-28 , DOI: 10.1016/j.dnarep.2019.102768
Yuqin Cai ₁ , Nicholas E Geacintov ₂ , Suse Broyde ₁

Affiliation

The packaging of DNA in nucleosomes presents a barrier for biological transactions including replication, transcription and repair. However, despite years of research, how the DNA is freed from the histone proteins and thereby allows the molecular machines to access the DNA remains poorly understood. We are interested in global genomic nucleotide excision repair (GG-NER). It is established that the histones are obstacles to this process, and DNA lesions are repaired less efficiently in nucleosomes than in free DNA. In the present study, we utilized molecular dynamics simulations to elucidate the nature of the distortions and dynamics imposed in the nucleosome by a set of three structually different lesions that vary in GG-NER efficiencies in free DNA, and in nucleosomes [Shafirovich, Geacintov, et. al, 2019]. Two of these are bulky lesions derived from metabolic activation of the environmental carcinogen benzo[a]pyrene, the 10R (+)-cis-anti-B[a]P-N2-dG and the stereoisomeric 10S (+)-trans-anti-B[a]P-N2-dG, which respectively adopt base-displaced/intercalated and minor groove-aligned conformations in DNA. The third is a non-bulky lesion, the 5'R-8-cyclo-2'-deoxyguanosine cross-link, produced by reactive oxygen and nitrogen species; cyclopurine lesions are highly mutagenic. These adducts are placed near the dyad axis, and rotationally with the lesion-containing strand facing towards or away from the histones. While each lesion has distinct conformational characteristics that are retained in the nucleosome, a spectrum of structural and dynamic disturbances, from slight to substantial, are displayed that depend on the lesion's structure and position in the nucleosome. We hypothesize that these intrinsic structural and dynamic distinctions provide different signals to initiate the cascade of chromatin-opening processes, including acetylation and other post translational modifications, remodeling by ATP-dependent complexes and spontaneous unwrapping that regulate the rate of access to the lesion; this may translate ultimately into varying GG-NER efficiencies, including repair resistance when signals for access are too weak.

中文翻译：

构象上不同的DNA损伤对核小体结构和动力学的可变影响：对核苷酸切除修复的影响。

DNA在核小体中的包装为生物交易（包括复制，转录和修复）提供了障碍。然而，尽管进行了多年的研究，如何从组蛋白中释放出DNA从而使分子机器访问DNA仍然知之甚少。我们对整体基因组核苷酸切除修复（GG-NER）感兴趣。已经确定，组蛋白是该过程的障碍，与游离DNA相比，核小体中DNA损伤的修复效率较低。在本研究中，我们利用分子动力学模拟来阐明由三种结构上不同的损伤在核小体中施加的畸变和动力学的性质，这些病变在游离DNA和核小体中具有不同的GG-NER效率[Shafirovich，Geacintov，等。al，2019]。其中两个是从环境致癌物苯并[a] py，10R（+）-顺-抗-B [a] P-N2-dG和立体异构体10S（+）-反-抗的代谢激活产生的大体积病变-B [a] P-N2-dG，它们分别在DNA中采用碱基置换/嵌入和小沟对齐构象。第三个是非大块病变，由活性氧和氮物种产生的5'R-8-环-2'-脱氧鸟苷交联；环嘌呤损伤高度致突变。将这些加合物置于二聚体轴附近，并旋转，使包含病变的股线朝向或远离组蛋白。尽管每个病变都有保留在核小体中的独特构象特征，但显示的结构和动态干扰（从轻度到严重）的范围取决于病变' 在核小体中的结构和位置。我们假设这些固有的结构和动态区别提供了不同的信号来启动染色质开放过程的级联，包括乙酰化和其他翻译后修饰，ATP依赖复合物的重塑和调节进入病变部位的自发性包裹。这最终可能会转化为各种GG-NER效率，包括访问信号太弱时的修复阻力。通过ATP依赖的复合物和自发解缠来重塑，从而调节进入病变的速度；这最终可能会转化为各种GG-NER效率，包括访问信号太弱时的修复阻力。通过ATP依赖的复合物和自发解缠来重塑，从而调节进入病变的速度；这最终可能会转化为各种GG-NER效率，包括访问信号太弱时的修复阻力。

更新日期：2019-12-29

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11