Ren Mengtian, Shang Mengdi, Wang Huawei, Xi Zhen, Zhou Chuanzheng
State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China.
Nucleic Acids Res. 2021 Jan 11;49(1):257-268. doi: 10.1093/nar/gkaa1153.
8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is a biomarker of oxidative DNA damage and can be repaired by hOGG1 and APE1 via the base excision repair (BER) pathway. In this work, we studied coordinated BER of 8-oxodGuo by hOGG1 and APE1 in nucleosome core particles and found that histones transiently formed DNA-protein cross-links (DPCs) with active repair intermediates such as 3'-phospho-α,β-unsaturated aldehyde (PUA) and 5'-deoxyribosephosphate (dRP). The effects of histone participation could be beneficial or deleterious to the BER process, depending on the circumstances. In the absence of APE1, histones enhanced the AP lyase activity of hOGG1 by cross-linking with 3'-PUA. However, the formed histone-PUA DPCs hampered the subsequent repair process. In the presence of APE1, both the AP lyase activity of hOGG1 and the formation of histone-PUA DPCs were suppressed. In this case, histones could catalyse removal of the 5'-dRP by transiently cross-linking with the active intermediate. That is, histones promoted the repair by acting as 5'-dRP lyases. Our findings demonstrate that histones participate in multiple steps of 8-oxodGuo repair in nucleosome core particles, highlighting the diverse roles that histones may play during DNA repair in eukaryotic cells.
8-氧代-7,8-二氢-2'-脱氧鸟苷（8-氧代-dGuo）是氧化DNA损伤的生物标志物，可通过碱基切除修复（BER）途径由hOGG1和APE1进行修复。在这项工作中，我们研究了hOGG1和APE1在核小体核心颗粒中对8-氧代-dGuo的协同BER，发现组蛋白与活性修复中间体如3'-磷酸-α,β-不饱和醛（PUA）和5'-脱氧核糖磷酸（dRP）瞬时形成DNA-蛋白质交联（DPC）。组蛋白参与的影响对BER过程可能有益也可能有害，这取决于具体情况。在没有APE1的情况下，组蛋白通过与3'-PUA交联增强了hOGG1的AP裂解酶活性。然而，形成的组蛋白-PUA DPC阻碍了随后的修复过程。在有APE1的情况下，hOGG1的AP裂解酶活性和组蛋白-PUA DPC的形成均受到抑制。在这种情况下，组蛋白可通过与活性中间体瞬时交联催化去除5'-dRP。也就是说，组蛋白作为5'-dRP裂解酶促进了修复。我们的研究结果表明，组蛋白参与了核小体核心颗粒中8-氧代-dGuo修复的多个步骤，突出了组蛋白在真核细胞DNA修复过程中可能发挥的多种作用。
