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

Author

Listed:
  • Weina Zhang

    (Tongji University
    Tongji University)

  • Mingzhu Wang

    (Tongji University
    Jiaxing University Affiliated Women and Children Hospital)

  • 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
    Tongji University
    China Pharmaceutical University)

  • Xiaojun Xu

    (China Pharmaceutical University)

  • Shaorong Gao

    (Tongji University)

  • Ying Jiang

    (Tongji University)

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.

Suggested Citation

  • 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 & , 2023. "Farrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37576-9
    DOI: 10.1038/s41467-023-37576-9
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    1. Kimiko Inoue & Narumi Ogonuki & Satoshi Kamimura & Hiroki Inoue & Shogo Matoba & Michiko Hirose & Arata Honda & Kento Miura & Masashi Hada & Ayumi Hasegawa & Naomi Watanabe & Yukiko Dodo & Keiji Mochi, 2020. "Loss of H3K27me3 imprinting in the Sfmbt2 miRNA cluster causes enlargement of cloned mouse placentas," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. Yingfeng Li & Zhuqiang Zhang & Jiayu Chen & Wenqiang Liu & Weiyi Lai & Baodong Liu & Xiang Li & Liping Liu & Shaohua Xu & Qiang Dong & Mingzhu Wang & Xiaoya Duan & Jiajun Tan & Yong Zheng & Pumin Zhan, 2018. "Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1," Nature, Nature, vol. 564(7734), pages 136-140, December.
    3. Mo Chen & Qianshu Zhu & Chong Li & Xiaochen Kou & Yanhong Zhao & Yanhe Li & Ruimin Xu & Lei Yang & Lingyue Yang & Liang Gu & Hong Wang & Xiaoyu Liu & Cizhong Jiang & Shaorong Gao, 2020. "Chromatin architecture reorganization in murine somatic cell nuclear transfer embryos," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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