Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 06 2023
23 06 2023
Historique:
received:
02
04
2022
accepted:
09
06
2023
medline:
26
6
2023
pubmed:
24
6
2023
entrez:
23
6
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37353483
doi: 10.1038/s41467-023-39374-9
pii: 10.1038/s41467-023-39374-9
pmc: PMC10290057
doi:
Substances chimiques
Topoisomerase I Inhibitors
0
pevonedistat
S3AZD8D215
Proteasome Endopeptidase Complex
EC 3.4.25.1
Ubiquitin
0
Ligases
EC 6.-
Ubiquitin-Protein Ligases
EC 2.3.2.27
DCAF13 protein, human
0
RNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3762Subventions
Organisme : Intramural NIH HHS
ID : Z01 BC006150
Pays : United States
Informations de copyright
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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