NEIL3通过促进下游双链断裂修复步骤，参与范可尼贫血/BRCA途径。

NEIL3 contributes to the Fanconi anemia/BRCA pathway by promoting the downstream double-strand break repair step.

作者信息

Li Niu, Xu Yufei, Chen Hongzhu, Chen Lina, Zhang Yi, Yu Tingting, Yao Ruen, Chen Jing, Fu Qihua, Zhou Jia, Wang Jian

机构信息

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai 200127, China.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.

出版信息

Cell Rep. 2022 Nov 8;41(6):111600. doi: 10.1016/j.celrep.2022.111600.

DOI:10.1016/j.celrep.2022.111600

PMID:36351389

Abstract

Interstrand crosslinks (ICLs) repair by the canonical Fanconi anemia (FA) pathway generates double-strand breaks (DSBs), which are subsequently repaired by the homologous recombination (HR) pathway. Recent studies show that the NEIL3 DNA glycosylase repairs psoralen-ICLs by direct unhooking. However, whether and how NEIL3 regulates MMC and cisplatin-ICL repair remains unclear. Here we show that NEIL3 participates in DSB repair step of ICL repair by promoting HR pathway. Mechanistically, NEIL3 is recruited to the DSB sites through its GRF zinc finger motifs. NEIL3 interacts with the DSB resection machinery, including CtIP, the MRE11-RAD50-NBS1 (MRN) complex, and DNA2, which is mediated by the GRF zinc finger motifs. In addition, NEIL3 is necessary for the chromatin recruitment of the resection machinery, and depletion of NEIL3 decreases end resection and compromises HR. Taken together, our results show that NEIL3 plays an important role in MMC/cisplatin-ICL repair by promoting the HR step in FA/BRCA pathway.

摘要

通过经典范可尼贫血（FA）途径进行的链间交联（ICL）修复会产生双链断裂（DSB），随后由同源重组（HR）途径进行修复。最近的研究表明，NEIL3 DNA糖基化酶通过直接解钩来修复补骨脂素-ICL。然而，NEIL3是否以及如何调节丝裂霉素和顺铂-ICL修复仍不清楚。在这里，我们表明NEIL3通过促进HR途径参与ICL修复的DSB修复步骤。从机制上讲，NEIL3通过其GRF锌指基序被招募到DSB位点。NEIL3与DSB切除机制相互作用，包括CtIP、MRE11-RAD50-NBS1（MRN）复合物和DNA2，这是由GRF锌指基序介导的。此外，NEIL3对于切除机制的染色质募集是必需的，并且NEIL3的缺失会减少末端切除并损害HR。综上所述，我们的结果表明，NEIL3通过促进FA/BRCA途径中的HR步骤在丝裂霉素/顺铂-ICL修复中起重要作用。