2. Academic Validation
  3. Farrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer

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

  • Nat Commun. 2023 Apr 3;14(1):1838. doi: 10.1038/s41467-023-37576-9.
Weina Zhang # 1 2,  Mingzhu Wang # 1 3,  Zhiwei Song # 1,  Qianzheng Fu # 1,  Jiayu Chen 1,  Weitao Zhang 4,  Shuai Gao 5,  Xiaoxiang Sun 1,  Guang Yang 1,  Qiang Zhang 5,  Jiaqing Yang 1,  Huanyin Tang 1,  Haiyan Wang 1,  Xiaochen Kou 1,  Hong Wang 1,  Zhiyong Mao 6 7 8,  Xiaojun Xu 9,  Shaorong Gao 10,  Ying Jiang 11
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, 200092, Shanghai, China.
  • 2 Tsingtao Advanced Research Institute, Tongji University, 266071, Qingdao, China.
  • 3 Jiaxing University Affiliated Women and Children Hospital, 314000, Jiaxing, China.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, China.
  • 5 Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China.
  • 6 Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, 200092, Shanghai, China. zhiyong_mao@tongji.edu.cn.
  • 7 Tsingtao Advanced Research Institute, Tongji University, 266071, Qingdao, China. zhiyong_mao@tongji.edu.cn.
  • 8 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, China. zhiyong_mao@tongji.edu.cn.
  • 9 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, China. xiaojunxu@cpu.edu.cn.
  • 10 Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, 200092, Shanghai, China. gaoshaorong@tongji.edu.cn.
  • 11 Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, 200092, Shanghai, China. ying_jiang@tongji.edu.cn.
  • # Contributed equally.
PMID: 37012254 DOI: 10.1038/s41467-023-37576-9
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.

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