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Hemi-methylated DNA opens a closed conformation of UHRF1 to facilitate its histone recognition

Author

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  • Jian Fang

    (Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University
    State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University
    Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University)

  • Jingdong Cheng

    (Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University)

  • Jiaolong Wang

    (State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences)

  • Qiao Zhang

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University)

  • Mengjie Liu

    (Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University)

  • Rui Gong

    (Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University)

  • Ping Wang

    (Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University)

  • Xiaodan Zhang

    (Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University)

  • Yangyang Feng

    (Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University)

  • Wenxian Lan

    (State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences)

  • Zhou Gong

    (State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences)

  • Chun Tang

    (State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences)

  • Jiemin Wong

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University)

  • Huirong Yang

    (Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University)

  • Chunyang Cao

    (State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences)

  • Yanhui Xu

    (Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University
    State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University
    Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University)

Abstract

UHRF1 is an important epigenetic regulator for maintenance DNA methylation. UHRF1 recognizes hemi-methylated DNA (hm-DNA) and trimethylation of histone H3K9 (H3K9me3), but the regulatory mechanism remains unknown. Here we show that UHRF1 adopts a closed conformation, in which a C-terminal region (Spacer) binds to the tandem Tudor domain (TTD) and inhibits H3K9me3 recognition, whereas the SET-and-RING-associated (SRA) domain binds to the plant homeodomain (PHD) and inhibits H3R2 recognition. Hm-DNA impairs the intramolecular interactions and promotes H3K9me3 recognition by TTD–PHD. The Spacer also facilitates UHRF1–DNMT1 interaction and enhances hm-DNA-binding affinity of the SRA. When TTD–PHD binds to H3K9me3, SRA-Spacer may exist in a dynamic equilibrium: either recognizes hm-DNA or recruits DNMT1 to chromatin. Our study reveals the mechanism for regulation of H3K9me3 and hm-DNA recognition by URHF1.

Suggested Citation

  • Jian Fang & Jingdong Cheng & Jiaolong Wang & Qiao Zhang & Mengjie Liu & Rui Gong & Ping Wang & Xiaodan Zhang & Yangyang Feng & Wenxian Lan & Zhou Gong & Chun Tang & Jiemin Wong & Huirong Yang & Chunya, 2016. "Hemi-methylated DNA opens a closed conformation of UHRF1 to facilitate its histone recognition," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11197
    DOI: 10.1038/ncomms11197
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