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Fanzor is a eukaryotic programmable RNA-guided endonuclease

Author

Listed:
  • Makoto Saito

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Peiyu Xu

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Guilhem Faure

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Samantha Maguire

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Soumya Kannan

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Han Altae-Tran

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Sam Vo

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • AnAn Desimone

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Rhiannon K. Macrae

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Feng Zhang

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research at MIT
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

Abstract

RNA-guided systems, which use complementarity between a guide RNA and target nucleic acid sequences for recognition of genetic elements, have a central role in biological processes in both prokaryotes and eukaryotes. For example, the prokaryotic CRISPR–Cas systems provide adaptive immunity for bacteria and archaea against foreign genetic elements. Cas effectors such as Cas9 and Cas12 perform guide-RNA-dependent DNA cleavage1. Although a few eukaryotic RNA-guided systems have been studied, including RNA interference2 and ribosomal RNA modification3, it remains unclear whether eukaryotes have RNA-guided endonucleases. Recently, a new class of prokaryotic RNA-guided systems (termed OMEGA) was reported4,5. The OMEGA effector TnpB is the putative ancestor of Cas12 and has RNA-guided endonuclease activity4,6. TnpB may also be the ancestor of the eukaryotic transposon-encoded Fanzor (Fz) proteins4,7, raising the possibility that eukaryotes are also equipped with CRISPR–Cas or OMEGA-like programmable RNA-guided endonucleases. Here we report the biochemical characterization of Fz, showing that it is an RNA-guided DNA endonuclease. We also show that Fz can be reprogrammed for human genome engineering applications. Finally, we resolve the structure of Spizellomyces punctatus Fz at 2.7 Å using cryogenic electron microscopy, showing the conservation of core regions among Fz, TnpB and Cas12, despite diverse cognate RNA structures. Our results show that Fz is a eukaryotic OMEGA system, demonstrating that RNA-guided endonucleases are present in all three domains of life.

Suggested Citation

  • Makoto Saito & Peiyu Xu & Guilhem Faure & Samantha Maguire & Soumya Kannan & Han Altae-Tran & Sam Vo & AnAn Desimone & Rhiannon K. Macrae & Feng Zhang, 2023. "Fanzor is a eukaryotic programmable RNA-guided endonuclease," Nature, Nature, vol. 620(7974), pages 660-668, August.
  • Handle: RePEc:nat:nature:v:620:y:2023:i:7974:d:10.1038_s41586-023-06356-2
    DOI: 10.1038/s41586-023-06356-2
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    Cited by:

    1. Xu Feng & Ruyi Xu & Jianglan Liao & Jingyu Zhao & Baochang Zhang & Xiaoxiao Xu & Pengpeng Zhao & Xiaoning Wang & Jianyun Yao & Pengxia Wang & Xiaoxue Wang & Wenyuan Han & Qunxin She, 2024. "Flexible TAM requirement of TnpB enables efficient single-nucleotide editing with expanded targeting scope," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Guoling Li & Xue Dong & Jiamin Luo & Tanglong Yuan & Tong Li & Guoli Zhao & Hainan Zhang & Jingxing Zhou & Zhenhai Zeng & Shuna Cui & Haoqiang Wang & Yin Wang & Yuyang Yu & Yuan Yuan & Erwei Zuo & Chu, 2024. "Engineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Dmitrii Degtev & Jack Bravo & Aikaterini Emmanouilidi & Aleksandar Zdravković & Oi Kuan Choong & Julia Liz Touza & Niklas Selfjord & Isabel Weisheit & Margherita Francescatto & Pinar Akcakaya & Michel, 2024. "Engineered PsCas9 enables therapeutic genome editing in mouse liver with lipid nanoparticles," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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