Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex
- PMID: 37353483
- PMCID: PMC10290057
- DOI: 10.1038/s41467-023-39374-9
Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex
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.
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Conflict of interest statement
The authors declare no competing interests.
Figures
Similar articles
-
NEDDylated Cullin 3 mediates the adaptive response to topoisomerase 1 inhibitors.Sci Adv. 2022 Dec 9;8(49):eabq0648. doi: 10.1126/sciadv.abq0648. Epub 2022 Dec 9. Sci Adv. 2022. PMID: 36490343 Free PMC article.
-
Suppression of autophagy during mitosis via CUL4-RING ubiquitin ligases-mediated WIPI2 polyubiquitination and proteasomal degradation.Autophagy. 2019 Nov;15(11):1917-1934. doi: 10.1080/15548627.2019.1596484. Epub 2019 Mar 30. Autophagy. 2019. PMID: 30898011 Free PMC article.
-
PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation.Nat Commun. 2021 Aug 18;12(1):5010. doi: 10.1038/s41467-021-25252-9. Nat Commun. 2021. PMID: 34408146 Free PMC article.
-
Cullin-RING E3 Ubiquitin Ligases: Bridges to Destruction.Subcell Biochem. 2017;83:323-347. doi: 10.1007/978-3-319-46503-6_12. Subcell Biochem. 2017. PMID: 28271482 Free PMC article. Review.
-
Targeting Protein Neddylation for Cancer Therapy.Adv Exp Med Biol. 2020;1217:297-315. doi: 10.1007/978-981-15-1025-0_18. Adv Exp Med Biol. 2020. PMID: 31898235 Review.
Cited by
-
miR-326 overexpression inhibits colorectal cancer cell growth and proteasome activity by targeting PNO1: unveiling a novel therapeutic intervention strategy.Sci Rep. 2024 Oct 16;14(1):24284. doi: 10.1038/s41598-024-75746-x. Sci Rep. 2024. PMID: 39414903 Free PMC article.
-
DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway.Cell Mol Life Sci. 2024 Oct 5;81(1):421. doi: 10.1007/s00018-024-05446-2. Cell Mol Life Sci. 2024. PMID: 39367995 Free PMC article.
-
Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential.Molecules. 2024 Sep 9;29(17):4280. doi: 10.3390/molecules29174280. Molecules. 2024. PMID: 39275127 Free PMC article. Review.
-
A Modular Biosensor Design for Quantitative Measurement of Free Nedd8.ACS Sens. 2024 Sep 27;9(9):4740-4747. doi: 10.1021/acssensors.4c01130. Epub 2024 Sep 10. ACS Sens. 2024. PMID: 39253816 Free PMC article.
-
The cullin Rtt101 promotes ubiquitin-dependent DNA-protein crosslink repair across the cell cycle.Nucleic Acids Res. 2024 Sep 9;52(16):9654-9670. doi: 10.1093/nar/gkae658. Nucleic Acids Res. 2024. PMID: 39077933 Free PMC article.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous