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

Abstract in brief

• Targeting neddylation, which involves modifying proteins with NEDD8, makes colorectal cancer cells more sensitive to topoisomerase I inhibitors like irinotecan by disrupting the activity of the DCAF13-CRL4 ubiquitin ligase complex.
• The study shows that combining topoisomerase I inhibitors with pevonedistat, an inhibitor of NEDD8 activation, enhances cancer cell death by preventing the repair of DNA-protein crosslinks caused by TOP1 inhibitors, through blocking the ubiquitin-proteasome pathway.
• Mechanistically, DCAF13 acts as a receptor for TOP1 DNA-protein crosslinks and recruits the CRL4 complex to mark these for degradation, a process that is hindered when neddylation is inhibited, suggesting a promising combined therapy approach for CRC and other cancers.