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The TDRD3-USP9X complex and MIB1 regulate TOP3B homeostasis and prevent deleterious TOP3B cleavage complexes

Author

Listed:
  • Sourav Saha

    (National Cancer Institute, NIH)

  • Shar-yin Naomi Huang

    (National Cancer Institute, NIH)

  • Xi Yang

    (National Cancer Institute, NIH)

  • Liton Kumar Saha

    (National Cancer Institute, NIH)

  • Yilun Sun

    (National Cancer Institute, NIH)

  • Prashant Khandagale

    (National Cancer Institute, NIH)

  • Lisa M. Jenkins

    (National Cancer Institute, NIH)

  • Yves Pommier

    (National Cancer Institute, NIH)

Abstract

TOP3B is stabilized by TDRD3. Hypothesizing that TDRD3 recruits a deubiquitinase, we find that TOP3B interacts with USP9X via TDRD3. Inactivation of USP9X destabilizes TOP3B, and depletion of both TDRD3 and USP9X does not promote further TOP3B ubiquitylation. Additionally, we observe that MIB1 mediates the ubiquitylation and proteasomal degradation of TOP3B by directly interacting with TOP3B independently of TDRD3. Combined depletion of USP9X, TDRD3 and MIB1 causes no additional increase in TOP3B levels compared to MIB1 knockdown alone indicating that the TDRD3-USP9X complex works downstream of MIB1. To comprehend why cells degrade TOP3B in the absence of TDRD3, we measured TOP3Bccs. Lack of TDRD3 increases TOP3Bccs in DNA and RNA, and induced R-loops, γH2AX and growth defect. Biochemical experiments confirm that TDRD3 increases the turnover of TOP3B. Our work provides molecular insights into the mechanisms by which TDRD3 protect cells from deleterious TOP3Bccs which are otherwise removed by TRIM41.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43151-z
    DOI: 10.1038/s41467-023-43151-z
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    References listed on IDEAS

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    1. 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.
    2. Seung Kyu Lee & Yutong Xue & Weiping Shen & Yongqing Zhang & Yuyoung Joo & Muzammil Ahmad & Madoka Chinen & Yi Ding & Wai Lim Ku & Supriyo De & Elin Lehrmann & Kevin G. Becker & Elissa P. Lei & Keji Z, 2018. "Topoisomerase 3β interacts with RNAi machinery to promote heterochromatin formation and transcriptional silencing in Drosophila," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
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