<p>WDFY2 promotes MRN complex formation required for homologous recombination-mediated DNA repair</p>

Lu, Ya-Fe F; Tang, Huangqi; Di, Longjiang; Yerkinkazhina, Yerkezhan; Su, Jiajie; Tang, Ming; Qian, Jinqin; Zeng, Rongsheng; Shu, Yuxin; He, Xingkai; Yang, Hui; Zhang, Jun; Tian, Yuan; Zhu, Qian; Zhang, Luyao; Wang, Yongqing; Ni, Dongchun; Pei, Xin-Ha H; Zhao, Ying; Leung, Chung-Han H; Lu, Xiaopeng; Zhu, Wei-Gu G

<p>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.</p>

WDFY2 promotes MRN complex formation required for homologous recombination-mediated DNA repair
Article (Faculty180)