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Structural and biochemical basis for DNA and RNA catalysis by human Topoisomerase 3β

Author

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  • Xi Yang

    (National Cancer Institute, NIH)

  • Sourav Saha

    (National Cancer Institute, NIH)

  • Wei Yang

    (National Institute of Diabetes and Digestive and Kidney Diseases, NIH)

  • Keir C. Neuman

    (National Institutes of Health)

  • Yves Pommier

    (National Cancer Institute, NIH)

Abstract

In metazoans, topoisomerase 3β (TOP3B) regulates R-loop dynamics and mRNA translation, which are critical for genome stability, neurodevelopment and normal aging. As a Type IA topoisomerase, TOP3B acts by general acid-base catalysis to break and rejoin single-stranded DNA. Passage of a second DNA strand through the transient break permits dissipation of hypernegative DNA supercoiling and catenation/knotting. Additionally, hsTOP3B was recently demonstrated as the human RNA topoisomerase, required for normal neurodevelopment and proposed to be a potential anti-viral target upon RNA virus infection. Here we elucidate the biochemical mechanisms of human TOP3B. We delineate the roles of divalent metal ions, and of a conserved Lysine residue (K10) in the differential catalysis of DNA and RNA. We also demonstrate that three regulatory factors fine-tune the catalytic performance of TOP3B: the TOP3B C-terminal tail, its protein partner TDRD3, and the sequence of its DNA/RNA substrates.

Suggested Citation

  • Xi Yang & Sourav Saha & Wei Yang & Keir C. Neuman & Yves Pommier, 2022. "Structural and biochemical basis for DNA and RNA catalysis by human Topoisomerase 3β," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32221-3
    DOI: 10.1038/s41467-022-32221-3
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    References listed on IDEAS

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    1. Anita Changela & Russell J. DiGate & Alfonso Mondragón, 2001. "Crystal structure of a complex of a type IA DNA topoisomerase with a single-stranded DNA molecule," Nature, Nature, vol. 411(6841), pages 1077-1081, June.
    2. Benjamin D. Bax & Pan F. Chan & Drake S. Eggleston & Andrew Fosberry & Daniel R. Gentry & Fabrice Gorrec & Ilaria Giordano & Michael M. Hann & Alan Hennessy & Martin Hibbs & Jianzhong Huang & Emma Jon, 2010. "Type IIA topoisomerase inhibition by a new class of antibacterial agents," Nature, Nature, vol. 466(7309), pages 935-940, August.
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    Cited by:

    1. Sourav Saha & Shar-yin Naomi Huang & Xi Yang & Liton Kumar Saha & Yilun Sun & Prashant Khandagale & Lisa M. Jenkins & Yves Pommier, 2023. "The TDRD3-USP9X complex and MIB1 regulate TOP3B homeostasis and prevent deleterious TOP3B cleavage complexes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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