Department of Chemistry, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, United States.
Thomas C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland 21218, United States.
J Am Chem Soc. 2022 May 4;144(17):7600-7605. doi: 10.1021/jacs.2c02880. Epub 2022 Apr 25.
Evaluating the significance of various forms of DNA damage is complicated by discoveries that some lesions inactivate repair enzymes or produce more deleterious forms of damage. Histone lysines within nucleosomes react with the commonly produced C4'-oxidized abasic site (C4-AP) to concomitantly yield an electrophilic modification (K) on lysine and DNA strand scission. We developed a chemoproteomic approach to identify K in HeLa cells. More than 60 000 K-modified histones are produced per cell. Using LC-MS/MS, we detected K at 17 of the 57 lysine residues distributed throughout the four core histone proteins. Therefore, K constitutes a DNA damage-induced, nonenzymatic histone post-translational modification. K formation suggests that downstream processes resulting from DNA damage could have ramifications on cells.
评估各种形式的 DNA 损伤的意义很复杂，因为有些损伤会使修复酶失活或产生更具危害性的损伤形式。核小体中的组蛋白赖氨酸与普遍产生的 C4'-氧化脱碱基位点（C4-AP）反应，同时在赖氨酸上产生亲电修饰（K）和 DNA 链断裂。我们开发了一种化学蛋白质组学方法来鉴定 HeLa 细胞中的 K。每个细胞产生超过 60000 个 K 修饰组蛋白。使用 LC-MS/MS，我们在四个核心组蛋白蛋白中分布的 57 个赖氨酸残基中的 17 个检测到 K。因此，K 构成了一种由 DNA 损伤诱导的、非酶促的组蛋白翻译后修饰。K 的形成表明，DNA 损伤导致的下游过程可能对细胞产生影响。
