尿嘧啶DNA糖基化酶通过不同于核糖核酸酶H2的机制修复嵌入DNA中的尿嘧啶，这一成果由南开大学周传政研究小组经过不懈努力而取得。该研究于2025年3月25日发表于国际一流学术期刊《美国化学会杂志》上。

在这项研究中，该研究团队报道了rU也通过UDG介导的BER途径进行修复。该团队发现UDG可以催化从DNA中嵌入的rU中去除尿嘧啶，但对RNA中的rU没有活性。生化和晶体学分析表明，rU的2'-OH基团被UDG有效调节，并直接参与催化N-糖苷键的水解。UDG从rU中去除尿嘧啶后产生的碱基产物被下游BER酶进一步加工以恢复未受损的DNA。他们的研究结果表明，UDG启动的BER构成了一个以前未被识别的修复rU特异性核糖核苷酸的途径。此外，研究小组开发了一种选择性定量DNA中rU含量的方法。通过这种方法，该团队确定UDG对rU的修复不是人类细胞的主要途径。这一发现扩大了他们对UDG多种生物学功能的理解，并激发了进一步的研究，以确定其在细胞中去除ru的作用。

研究人员表示，尿嘧啶（rU）和2'-脱氧尿嘧啶（dU）是常见的DNA病变。dU通过尿嘧啶DNA糖基化酶（UDG）启动的碱基切除修复（BER）途径修复，而rU通常通过RNA酶H2介导的核糖核苷酸切除修复从DNA中去除。

附：英文原文

Title: Uridine Embedded within DNA is Repaired by Uracil DNA Glycosylase via a Mechanism Distinct from That of Ribonuclease H2

Author: Chaochao Fan, Xuelin Zhan, Fengmin Guo, Qiang Li, Kuan Lu, Xiajing Shan, Yifei Zhou, Mengtian Ren, Marc M. Greenberg, Yijin Liu, Chuanzheng Zhou

Issue&Volume: March 25, 2025

Abstract: Uridine (rU) and 2′-deoxyuridine (dU) are common DNA lesions. dU is repaired through a base excision repair (BER) pathway initiated by uracil DNA glycosylase (UDG), while rU is typically removed from DNA via ribonucleotide excision repair, mediated by RNase H2. In this study, we report that rU is also repaired through the UDG-mediated BER pathway. We found that UDG catalyzes the removal of uracil from rU embedded in DNA, but exhibits no activity toward rU in RNA. Biochemical and crystallographic analyses revealed that the 2′–OH group of rU is effectively accommodated by UDG and directly participates in catalyzing the hydrolysis of the N-glycosidic bond. The abasic site product generated upon removal of uracil from rU by UDG is further processed by downstream BER enzymes to restore undamaged DNA. Our findings suggest that UDG-initiated BER constitutes a previously unrecognized pathway for the repair of rU-specific ribonucleotides. Additionally, we developed a method for selectively quantifying rU content in DNA. Using this method, we determined that rU repair by UDG is not a major pathway in human cells. This discovery expands our understanding of the diverse biological functions of UDG, and inspires further investigation to determine the role of its rU-removal in cells.

DOI: 10.1021/jacs.5c01436

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c01436