Nucleosome Core Particles Lacking H2B or H3 Tails Are Altered Structurally and Have Differential Base Excision Repair Fingerprints
Nucleosome Core Particles Lacking H2B or H3 Tails Are Altered Structurally and Have Differential Base Excision Repair Fingerprints
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DOI：
10.1021/acs.biochem.0c00877
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发表时间：
2021-01-10
期刊：
影响因子：
2.9
通讯作者：
Delaney, Sarah
中科院分区：
文献类型：
--
作者：
Caffrey, Paul J.;Delaney, Sarah
最近发现的组蛋白翻译后修饰是组蛋白n端尾部结构域的不可逆蛋白水解剪切。这种修饰参与多种生物过程的调控，包括DNA损伤反应。在这项工作中，我们使用化学足迹来表征由于缺乏组蛋白H2B或H3尾部而导致的核小体核心颗粒（ncp）的结构改变。我们还研究了这些组蛋白尾部对修复酶烷基腺嘌呤DNA糖基化酶切除致突变病变1，n -6-乙烯腺嘌呤（epsilon A）的影响。我们发现，与天然ncp相比，缺少H2B或H3尾部导致DNA周期性改变。我们利用对ncp和未合并双工DNA中的21个epsilon A位点的全局分析，将这些结构改变与epsilon A切除联系起来。与天然ncp相比，无尾H2B ncp在DNA展开区域的epsilon A切除增强。无尾H3 ncp没有观察到这种增强的切除；相反，在不容易展开的NCP的静态区域，切除被抑制。我们的研究结果支持了烷基化损伤的体内观察，以及尾夹作为克服ncp中包装引起的物理障碍的机制的潜在作用，但也揭示了尾夹在某些位置对修复的潜在抑制。综上所述，这些结果进一步加深了我们对碱基切除修复如何通过组蛋白尾部去除来促进或减少的理解，并有助于我们理解导致突变热点的潜在机制。
A recently discovered post-translational modification of histone proteins is the irreversible proteolytic clipping of the histone N-terminal tail domains. This modification is involved in the regulation of various biological processes, including the DNA damage response. In this work, we used chemical footprinting to characterize the structural alterations to nucleosome core particles (NCPs) that result from a lack of a histone H2B or H3 tail. We also examine the influence of these histone tails on excision of the mutagenic lesion 1,N-6-ethenoadenine (epsilon A) by the repair enzyme alkyladenine DNA glycosylase. We found that the absence of the H2B or H3 tail results in altered DNA periodicity relative to that of native NCPs. We correlated these structural alterations to epsilon A excision by utilizing a global analysis of 21 epsilon A sites in NCPs and unincorporated duplex DNA. In comparison to native NCPs, there is enhanced excision of epsilon A in tailless H2B NCPs in regions that undergo DNA unwrapping. This enhanced excision is not observed for tailless H3 NCPs; rather, excision is inhibited in more static areas of the NCP not prone to unwrapping. Our results support in vivo observations of alkylation damage profiles and the potential role of tail clipping as a mechanism for overcoming physical obstructions caused by packaging in NCPs but also reveal the potential inhibition of repair by tail clipping in some locations. Taken together, these results further our understanding of how base excision repair can be facilitated or diminished by histone tail removal and contribute to our understanding of the underlying mechanism that leads to mutational hot spots.