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Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex

Author

Listed:
  • Yilun Sun

    (National Institutes of Health)

  • Simone A. Baechler

    (National Institutes of Health)

  • Xiaohu Zhang

    (National Institutes of Health)

  • Suresh Kumar

    (National Institutes of Health)

  • Valentina M. Factor

    (National Institutes of Health)

  • Yasuhiro Arakawa

    (National Institutes of Health)

  • Cindy H. Chau

    (National Institutes of Health)

  • Kanako Okamoto

    (National Institutes of Health)

  • Anup Parikh

    (National Institutes of Health)

  • Bob Walker

    (National Institutes of Health)

  • Yijun P. Su

    (National Institutes of Health)

  • Jiji Chen

    (National Institutes of Health)

  • Tabitha Ting

    (University of Texas Southwestern Medical Center)

  • Shar-yin N. Huang

    (National Institutes of Health)

  • Erin Beck

    (National Institutes of Health)

  • Zina Itkin

    (National Institutes of Health)

  • Crystal McKnight

    (National Institutes of Health)

  • Changqing Xie

    (National Institutes of Health)

  • Nitin Roper

    (National Institutes of Health)

  • Deepak Nijhawan

    (National Institutes of Health)

  • William Douglas Figg

    (National Institutes of Health)

  • Paul S. Meltzer

    (National Institutes of Health)

  • James C. Yang

    (National Institutes of Health)

  • Craig J. Thomas

    (National Institutes of Health)

  • Yves Pommier

    (National Institutes of Health)

Abstract

Colorectal cancers (CRCs) are prevalent worldwide, yet current treatments remain inadequate. Using chemical genetic screens, we identify that co-inhibition of topoisomerase I (TOP1) and NEDD8 is synergistically cytotoxic in human CRC cells. Combination of the TOP1 inhibitor irinotecan or its bioactive metabolite SN38 with the NEDD8-activating enzyme inhibitor pevonedistat exhibits synergy in CRC patient-derived organoids and xenografts. Mechanistically, we show that pevonedistat blocks the ubiquitin/proteasome-dependent repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) induced by TOP1 inhibitors and that the CUL4-RBX1 complex (CRL4) is a prominent ubiquitin ligase acting on TOP1-DPCs for proteasomal degradation upon auto-NEDD8 modification during replication. We identify DCAF13, a DDB1 and Cullin Associated Factor, as the receptor of TOP1-DPCs for CRL4. Our study not only uncovers a replication-coupled ubiquitin-proteasome pathway for the repair of TOP1-DPCs but also provides molecular and translational rationale for combining TOP1 inhibitors and pevonedistat for CRC and other types of cancers.

Suggested Citation

  • Yilun Sun & Simone A. Baechler & Xiaohu Zhang & Suresh Kumar & Valentina M. Factor & Yasuhiro Arakawa & Cindy H. Chau & Kanako Okamoto & Anup Parikh & Bob Walker & Yijun P. Su & Jiji Chen & Tabitha Ti, 2023. "Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39374-9
    DOI: 10.1038/s41467-023-39374-9
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    References listed on IDEAS

    as
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