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WDFY2 promotes MRN complex formation required for homologous recombination-mediated DNA repair.

Ya-Fei Lu·Huangqi Tang·Longjiang Di·Yerkezhan Yerkinkazhina·Jiajie Su·Ming Tang·Jinqin Qian·Rongsheng Zeng·Yuxin Shu·Xingkai He·Hui Yang·Jun Zhang·Yuan Tian·Qian Zhu·Luyao Zhang·Yongqing Wang·Dongchun Ni·Xin-Hai Pei·Ying Zhao·Chung-Hang Leung·Xiaopeng Lu·Wei-Guo Zhu
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Abstract

The MRE11-RAD50-NBS1 (MRN) complex is fundamental for detecting and repairing DNA double-strand breaks (DSBs), thereby safeguarding genome integrity. However, the precise mechanism governing MRN complex recruitment to DSBs remains largely unexplored. Here, we identify WD40- and FYVE domain-containing protein 2 (WDFY2) as an important regulator of MRN complex formation at DNA damage sites, facilitating homologous recombination (HR) repair. Mechanistically, WDFY2 is phosphorylated at serine 84 by the ATM-CHK2 axis, priming it for recruitment to DSBs. Through direct interactions with MRE11 and NBS1, WDFY2 bridges the MRE11-RAD50 subcomplex with NBS1, thereby promoting MRN complex formation at DSBs and DNA end resection. WDFY2 deficiency, as well as the non-phosphorylatable S84A mutant, results in impaired HR repair and reduced cell survival following DNA damage. Collectively, our findings establish WDFY2 as a key platform for MRN complex loading at DSBs and HR repair, highlighting it as a potential therapeutic target for cancer treatment.

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HumansMRE11 Homologue ProteinRecombinational DNA RepairDNA-Binding ProteinsDNA Breaks, Double-StrandedCell Cycle ProteinsPhosphorylationNuclear ProteinsDNA Repair EnzymesAtaxia Telangiectasia Mutated ProteinsAcid Anhydride HydrolasesAnimalsCheckpoint Kinase 2HEK293 CellsHomologous RecombinationMiceMultiprotein ComplexesATM-CHK2 axisCP: molecular biologyDNA double-strand breaksMRN complexWDFY2homologous recombinationJournal ArticleResearch Support, Non-U.S. Gov't

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Ya-Fei Lu, Huangqi Tang, Longjiang Di, Yerkezhan Yerkinkazhina, Jiajie Su, Ming Tang, Jinqin Qian, Rongsheng Zeng, Yuxin Shu, Xingkai He, Hui Yang, Jun Zhang, Yuan Tian, Qian Zhu, Luyao Zhang, Yongqing Wang, Dongchun Ni, Xin-Hai Pei, Ying Zhao, Chung-Hang Leung, Xiaopeng Lu, Wei-Guo Zhu. 2025-11-04. WDFY2 promotes MRN complex formation required for homologous recombination-mediated DNA repair.. https://doi.org/10.1016/j.celrep.2025.116520

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