Base-flipping dynamics from an intrahelical to an extrahelical state exerted by thymine DNA glycosylase during DNA repair process.
Base-flipping dynamics from an intrahelical to an extrahelical state exerted by thymine DNA glycosylase during DNA repair process.
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DNA修复过程中胸腺嘧啶DNA糖基化酶从螺旋内到螺旋外状态的碱基翻转动力学
DOI：
10.1093/nar/gky386
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发表时间：
2018-06-20
影响因子：
14.9
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Da LT;Yu J
胸腺嘧啶DNA糖基化酶（TDG）是一种DNA修复酶，它能切除各种错配或损伤的核苷酸（nts），如dU、dT、5fC和5caC。TDG被证明在维持基因组完整性和通过DNA去甲基化正确编程表观遗传修饰中发挥重要作用。在定位病变后，TDG采用碱基翻转策略来识别受损的核碱基，由此询问的nt从DNA螺旋堆叠中挤出并结合到TDG活性位点中。然而，在原子分辨率下碱基翻转过程的动力学机制仍然难以捉摸。在这里，我们采用马尔可夫状态模型（MSM）构建广泛的全原子分子动力学（MD）模拟揭示了完整的碱基翻转过程的G.T错配在几十微秒的时间尺度。我们的研究确定了错配dT在其挤出过程中的关键中间体，并揭示了参与状态间转换的关键TDG残基。值得注意的是，我们发现TDG在促进螺旋内nt外翻，雕刻DNA骨架和渗透到DNA小沟中的积极作用。三个额外的TDG基板，即dU，5fC，和5caC，进一步测试，以评估取代基的嘧啶环上的碱基翻转动力学的各种化学修饰的影响。
Abstract Thymine DNA glycosylase (TDG) is a DNA repair enzyme that excises a variety of mismatched or damaged nucleotides (nts), e.g. dU, dT, 5fC and 5caC. TDG is shown to play essential roles in maintaining genome integrity and correctly programming epigenetic modifications through DNA demethylation. After locating the lesions, TDG employs a base-flipping strategy to recognize the damaged nucleobases, whereby the interrogated nt is extruded from the DNA helical stack and binds into the TDG active site. The dynamic mechanism of the base-flipping process at an atomistic resolution, however, remains elusive. Here, we employ the Markov State Model (MSM) constructed from extensive all-atom molecular dynamics (MD) simulations to reveal the complete base-flipping process for a G.T mispair at a tens of microsecond timescale. Our studies identify critical intermediates of the mispaired dT during its extrusion process and reveal the key TDG residues involved in the inter-state transitions. Notably, we find an active role of TDG in promoting the intrahelical nt eversion, sculpturing the DNA backbone, and penetrating into the DNA minor groove. Three additional TDG substrates, namely dU, 5fC, and 5caC, are further tested to evaluate the substituent effects of various chemical modifications of the pyrimidine ring on base-flipping dynamics.
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作者：
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