Department of Chemistry, Johns Hopkins University, Baltimore, MD, 21218, USA.
Chembiochem. 2019 Jan 2;20(1):78-82. doi: 10.1002/cbic.201800559. Epub 2018 Nov 15.
Abasic sites (AP) are produced 10 000 times per day in a single cell. Strand cleavage at AP is accelerated ≈100-fold within a nucleosome core particle (NCP) compared to free DNA. The lysine-rich N-terminal tails of histone proteins catalyze single-strand breaks through a mechanism used by base-excision-repair enzymes, despite the general dearth of glutamic acid, aspartic acid, and histidine-the amino acids that are typically responsible for deprotonation of Schiff base intermediates. Incorporating glutamic acid, aspartic acid, or histidine proximal to lysine residues in histone N-terminal tails increases AP reactivity as much as sixfold. The rate acceleration is due to more facile DNA cleavage of Schiff-base intermediates. These observations raise the possibility that histone proteins could have evolved to minimize the presence of histidine, glutamic acid, and aspartic acid in their lysine-rich N-terminal tails to guard against enhancing the toxic effects of DNA damage.
堿基位点（AP）在单个细胞中每天产生 10000 次。与游离 DNA 相比，AP 处的链断裂在核小体核心颗粒（NCP）内的速度加快了 ≈100 倍。组蛋白蛋白富含赖氨酸的 N 端尾巴通过碱基切除修复酶使用的机制催化单链断裂，尽管谷氨酸、天冬氨酸和组氨酸通常负责去质子化 Schiff 碱中间体的氨基酸普遍缺乏。在组蛋白 N 端尾巴中的赖氨酸附近掺入谷氨酸、天冬氨酸或组氨酸会使 AP 反应性增加多达六倍。这种速率加速是由于 Schiff 碱中间体更容易进行 DNA 切割。这些观察结果提出了一种可能性，即组蛋白蛋白可能已经进化为在富含赖氨酸的 N 端尾巴中最小化组氨酸、谷氨酸和天冬氨酸的存在，以防止增强 DNA 损伤的毒性作用。
