2. Academic Validation
  3. WDFY2 promotes MRN complex formation required for homologous recombination-mediated DNA repair

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

  • Cell Rep. 2025 Nov 25;44(11):116520. doi: 10.1016/j.celrep.2025.116520.
Ya-Fei Lu 1,  Huangqi Tang 1,  Longjiang Di 1,  Yerkezhan Yerkinkazhina 1,  Jiajie Su 1,  Ming Tang 2,  Jinqin Qian 1,  Rongsheng Zeng 1,  Yuxin Shu 3,  Xingkai He 1,  Hui Yang 1,  Jun Zhang 1,  Yuan Tian 1,  Qian Zhu 1,  Luyao Zhang 4,  Yongqing Wang 5,  Dongchun Ni 1,  Xin-Hai Pei 6,  Ying Zhao 7,  Chung-Hang Leung 8,  Xiaopeng Lu 9,  Wei-Guo Zhu 10
Affiliations

Affiliations

  • 1 International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China.
  • 2 Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 3 School of Basic Medical Sciences, Wannan Medical College, Wuhu 241002, China.
  • 4 Center of Biotherapy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.
  • 5 Division of Rheumatology and Immunology, University of Toledo Medical Center, Toledo, OH 43614, USA.
  • 6 International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Anatomy and Histology, Shenzhen University Medical School, Shenzhen 518055, China.
  • 7 Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 8 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
  • 9 International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China. Electronic address: [email protected].
  • 10 International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China; School of Basic Medical Sciences, Wannan Medical College, Wuhu 241002, China. Electronic address: [email protected].
PMID: 41196680 DOI: 10.1016/j.celrep.2025.116520
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.

Keywords

ATM-CHK2 axis; CP: molecular biology; DNA double-strand breaks; MRN complex; WDFY2; homologous recombination.

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