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Replication-associated formation and repair of human topoisomerase IIIα cleavage complexes

Author

Listed:
  • Liton Kumar Saha

    (NIH)

  • Sourav Saha

    (NIH)

  • Xi Yang

    (NIH)

  • Shar-yin Naomi Huang

    (NIH)

  • Yilun Sun

    (NIH)

  • Ukhyun Jo

    (NIH)

  • Yves Pommier

    (NIH)

Abstract

Topoisomerase IIIα (TOP3A) belongs to the conserved Type IA family of DNA topoisomerases. Here we report that human TOP3A is associated with DNA replication forks and that a “self-trapping” TOP3A mutant (TOP3A-R364W) generates cellular TOP3A DNA cleavage complexes (TOP3Accs). We show that trapped TOP3Accs that interfere with replication, induce DNA damage and genome instability. To elucidate how TOP3Accs are repaired, we explored the role of Spartan (SPRTN), the metalloprotease associated with DNA replication, which digests proteins forming DNA-protein crosslinks (DPCs). We find that SPRTN-deficient cells show elevated TOP3Accs, whereas overexpression of SPRTN lowers cellular TOP3Accs. SPRTN is deubiquitinated and epistatic with TDP2 in response to TOP3Accs. In addition, we found that MRE11 can excise TOP3Accs, and that cell cycle determines the preference for the SPRTN-TDP2 vs. the ATM-MRE11 pathways, in S vs. G2, respectively. Our study highlights the prevalence of TOP3Accs repair mechanisms to ensure normal DNA replication.

Suggested Citation

  • Liton Kumar Saha & Sourav Saha & Xi Yang & Shar-yin Naomi Huang & Yilun Sun & Ukhyun Jo & Yves Pommier, 2023. "Replication-associated formation and repair of human topoisomerase IIIα cleavage complexes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37498-6
    DOI: 10.1038/s41467-023-37498-6
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    References listed on IDEAS

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    1. Ann-Marie K. Shorrocks & Samuel E. Jones & Kaima Tsukada & Carl A. Morrow & Zoulikha Belblidia & Johanna Shen & Iolanda Vendrell & Roman Fischer & Benedikt M. Kessler & Andrew N. Blackford, 2021. "The Bloom syndrome complex senses RPA-coated single-stranded DNA to restart stalled replication forks," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Haiqing Fu & Christophe E. Redon & Bhushan L. Thakur & Koichi Utani & Robin Sebastian & Sang-Min Jang & Jacob M. Gross & Sara Mosavarpour & Anna B. Marks & Sophie Z. Zhuang & Sarah B. Lazar & Mishal R, 2021. "Dynamics of replication origin over-activation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Yusuke Kojima & Yuka Machida & Sowmiya Palani & Thomas R. Caulfield & Evette S. Radisky & Scott H. Kaufmann & Yuichi J. Machida, 2020. "FAM111A protects replication forks from protein obstacles via its trypsin-like domain," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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