TY - JOUR
T1 - Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex
AU - Sun, Yilun
AU - Baechler, Simone A.
AU - Zhang, Xiaohu
AU - Kumar, Suresh
AU - Factor, Valentina M.
AU - Arakawa, Yasuhiro
AU - Chau, Cindy H.
AU - Okamoto, Kanako
AU - Parikh, Anup
AU - Walker, Bob
AU - Su, Yijun P.
AU - Chen, Jiji
AU - Ting, Tabitha
AU - Huang, Shar yin N.
AU - Beck, Erin
AU - Itkin, Zina
AU - McKnight, Crystal
AU - Xie, Changqing
AU - Roper, Nitin
AU - Nijhawan, Deepak
AU - Figg, William Douglas
AU - Meltzer, Paul S.
AU - Yang, James C.
AU - Thomas, Craig J.
AU - Pommier, Yves
N1 - Funding Information:
This study was in part supported by the Center for Cancer Research, the Intramural Program of the NCI (Z01 BC 006150) to Y.P., and by the NCI Center for Cancer Research Excellence in Postdoctoral Research Transition Award and the NCI K99 Pathway to Independence Award (1K99 CA 273171) to Y.S.
Funding Information:
Open Access funding provided by the National Institutes of Health (NIH).
Publisher Copyright:
© 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85162839905&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-39374-9
DO - 10.1038/s41467-023-39374-9
M3 - Article
C2 - 37353483
AN - SCOPUS:85162839905
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3762
ER -