Farrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer

Weina Zhang, Mingzhu Wang, Zhiwei Song, Qianzheng Fu, Jiayu Chen, Weitao Zhang, Shuai Gao, Xiaoxiang Sun, Guang Yang, Qiang Zhang, Jiaqing Yang, Huanyin Tang, Haiyan Wang, Xiaochen Kou, Hong Wang, Zhiyong Mao (), Xiaojun Xu (), Shaorong Gao () and Ying Jiang ()
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Weina Zhang: Tongji University
Mingzhu Wang: Tongji University
Zhiwei Song: Tongji University
Qianzheng Fu: Tongji University
Jiayu Chen: Tongji University
Weitao Zhang: China Pharmaceutical University
Shuai Gao: China Agricultural University
Xiaoxiang Sun: Tongji University
Guang Yang: Tongji University
Qiang Zhang: China Agricultural University
Jiaqing Yang: Tongji University
Huanyin Tang: Tongji University
Haiyan Wang: Tongji University
Xiaochen Kou: Tongji University
Hong Wang: Tongji University
Zhiyong Mao: Tongji University
Xiaojun Xu: China Pharmaceutical University
Shaorong Gao: Tongji University
Ying Jiang: Tongji University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Farrerol, a natural flavanone, promotes homologous recombination (HR) repair to improve genome-editing efficiency, but the specific protein that farrerol directly targets to regulate HR repair and the underlying molecular mechanisms have not been determined. Here, we find that the deubiquitinase UCHL3 is the direct target of farrerol. Mechanistically, farrerol enhanced the deubiquitinase activity of UCHL3 to promote RAD51 deubiquitination, thereby improving HR repair. Importantly, we find that embryos of somatic cell nuclear transfer (SCNT) exhibited defective HR repair, increased genomic instability and aneuploidy, and that the farrerol treatment post nuclear transfer enhances HR repair, restores transcriptional and epigenetic network, and promotes SCNT embryo development. Ablating UCHL3 significantly attenuates farrerol-mediated stimulation in HR and SCNT embryo development. In summary, we identify farrerol as an activator of the deubiquitinase UCHL3, highlighted the importance of HR and epigenetic changes in SCNT reprogramming and provide a feasible method to promote SCNT efficiency.

Date: 2023
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DOI: 10.1038/s41467-023-37576-9

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