MRNIP condensates promote DNA double-strand break sensing and end resection

Yun-Long Wang, Wan-Wen Zhao, Shao-Mei Bai, Li-Li Feng, Shu-Ying Bie, Li Gong, Fang Wang, Ming-Biao Wei, Wei-Xing Feng, Xiao-Lin Pang, Cao-Litao Qin, Xin-Ke Yin, Ying-Nai Wang, Weihua Zhou, Daniel R. Wahl, Quentin Liu, Ming Chen (), Mien-Chie Hung () and Xiang-Bo Wan ()
Additional contact information
Yun-Long Wang: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Wan-Wen Zhao: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Shao-Mei Bai: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Li-Li Feng: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Shu-Ying Bie: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Li Gong: Sun Yat-sen University
Fang Wang: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Ming-Biao Wei: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Wei-Xing Feng: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Xiao-Lin Pang: the Sixth Affiliated Hospital, Sun Yat-sen University
Cao-Litao Qin: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Xin-Ke Yin: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
Ying-Nai Wang: The University of Texas MD Anderson Cancer Center
Weihua Zhou: University of Michigan
Daniel R. Wahl: University of Michigan
Quentin Liu: Dalian Medical University
Ming Chen: Sun Yat-sen University
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center
Xiang-Bo Wan: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection.

Date: 2022
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DOI: 10.1038/s41467-022-30303-w

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