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

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 Ting, Shar-yin N. Huang, Erin Beck, Zina Itkin, Crystal McKnight, Changqing Xie, Nitin Roper, Deepak Nijhawan, William Douglas Figg, Paul S. Meltzer, James C. Yang, Craig J. Thomas and Yves Pommier ()
Additional contact information
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

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39374-9

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