DNA-Protein Cross-Link Formation in Nucleosome Core Particles Treated with Methyl Methanesulfonate.
DNA-Protein Cross-Link Formation in Nucleosome Core Particles Treated with Methyl Methanesulfonate.
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DOI：
10.1021/acs.chemrestox.9b00314
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发表时间：
2019-09
影响因子：
4.1
通讯作者：
Kun Yang;M. Greenberg
中科院分区：
文献类型：
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作者：
Kun Yang;M. Greenberg
N7-甲基-2'-脱氧鸟苷 (MdG) 是甲基化剂产生的 DNA 中的主要损伤产物，但它通常被认为是无毒且无致突变性的。 MdG 化学性质不稳定。无碱基位点 (AP) 是 MdG 在生理相关条件下产生的主要产物。 AP 的形成通常被认为是 MdG 细胞毒性作用的原因，但该反应在核小体核心颗粒 (NCP) 中受到抑制。最近，人们发现，在重建的 NCP 以及甲基磺酸 (MMS) 处理的细胞中，组蛋白与 MdG 形成可逆的 DNA 蛋白交联 (DPC)。在本研究中，以单核苷酸分辨率检查了 MMS 处理的 NCP 中 MdG 的形成和反应性。由三个或更多连续 dG 组成的序列对 MMS 的反应性更强。 MMS 形成 MdG 的效率和选择性在 NCP 内基本上不受影响，尽管 NCP 中几个 dG 的反应性高出约 1.5-2.5 倍。在 NCP 内的所有位置，由 MdG (DPCMdG) 形成的 DPC 均优于 AP。除少数例外，DPCMdG 产量强烈依赖于含有 MdG 的主沟与富含赖氨酸的组蛋白 N 末端尾部的可及性。这些数据表明组蛋白-MdG DPC 的形成将取决于 NCP 内的 DNA 序列和翻译位置。
N7-Methyl-2'-deoxyguanosine (MdG) is the major damage product in DNA produced by methylating agents, but it often thought to be nontoxic and nonmutagenic. MdG is chemically unstable. An abasic site (AP) is the major product produced from MdG under physiologically relevant conditions. AP formation is frequently considered to be responsible for the cytotoxic effects of MdG, but the reaction is suppressed in nucleosome core particles (NCPs). Recently, it was discovered that histone proteins form reversible DNA-protein cross-links (DPCs) with MdG in reconstituted NCPs, as well as in methylmethanesulfonate (MMS) treated cells. In this study, the formation and reactivity of MdG in MMS treated NCPs was examined at single nucleotide resolution. Sequences consisting of three or more consecutive dGs are more reactive with MMS. The efficiency and selectivity of MdG formation by MMS is largely unaffected within a NCP, although reactivity at several dGs is ∼1.5-2.5-fold higher in NCPs. DPC formation from MdG (DPCMdG) predominates over AP at all positions within the NCP. With few exceptions, DPCMdG yield is strongly dependent upon the accessibility of the major groove containing MdG to lysine-rich histone N-terminal tails. These data indicate that histone-MdG DPC formation will depend upon DNA sequence and translational position within an NCP.