美国国立卫生研究院杨薇小组探明了切口前结构揭示了DNA核苷酸切除修复的原理。这一研究成果发表在2026年2月11日出版的国际学术期刊《自然》上。

在这里，研究人员报道了ATP酶驱动和病变依赖的DNA泡形成的功能步骤和原子结构，以及双切口完整NER因子的排列。近30DNA碱基对的形成主要依赖于DNA双链转位酶XPB和双链分割器XPA和XPF。XPD将病变链与XPF结合在5′ ds-ss连接处。XPF仅在XPG结合3′ ds-ss结后才切断病变链。XPF的ERCC1亚基促进DNA链分离和RPA招募到非损伤链。这些发现为人类疾病的发病机制和提高化疗疗效的潜在靶点提供了新的见解。

据悉，核苷酸切除修复（NER）从基因组DNA中去除庞大的加合物，并防止紫外光敏感性疾病着色性干皮病、癌症和过早衰老。在全球基因组修复过程中，XPC或转录偶联修复过程中停滞的RNA聚合酶对病灶进行初始识别后，病灶及其周围的DNA双链被TFIIH展开，TFIIH包括ATP酶XPB和XPD，以及额外的NER因子XPA、XPF、XPG和RPA，形成一个包含约27个核苷酸的DNA泡。双链-单链（ds-ss）连接特异性内切酶XPF和XPG分别在病变的5′和3′侧切割DNA。

附：英文原文

Title: Pre-incision structures reveal principles of DNA nucleotide excision repair

Author: Li, Eric C. L., Kim, Jinseok, Brussee, Sem J., Sugasawa, Kaoru, Luijsterburg, Martijn S., Yang, Wei

Issue&Volume: 2026-02-11

Abstract: Nucleotide excision repair (NER) removes bulky adducts from genomic DNA and prevents the ultraviolet light-sensitivity disease xeroderma pigmentosum, cancer and premature ageing1. After initial lesion recognition by XPC in global genome repair or by stalled RNA polymerases in transcription-coupled repair, a lesion and surrounding DNA duplex are unwound by TFIIH, which includes the ATPases XPB and XPD, and additional NER factors XPA, XPF, XPG and RPA, to form a DNA bubble2 comprising around 27 nucleotides. The double strand–single strand (ds-ss) junction-specific endonucleases XPF and XPG cleave DNA on the 5′ and 3′ sides of the lesion, respectively. Here we report the functional steps and atomic structures of the ATPase-driven and lesion-dependent DNA bubble formation and arrangement of the complete NER factors for dual incision. The unwinding of nearly 30base pairs of DNA depends mainly on the double strand DNA translocase XPB and the duplex dividers XPA and XPF. XPD binds the lesion strand with XPF at the 5′ ds-ss junction. XPF cuts the lesion strand only after XPG binds the 3′ ds-ss junction. The ERCC1 subunit of XPF facilitates DNA strand separation and recruitment of RPA to the non-lesion strand. These findings provide insights on the causes of human diseases and potential targets for enhancing chemotherapeutic efficacy.

DOI: 10.1038/s41586-026-10122-5

Source: https://www.nature.com/articles/s41586-026-10122-5