CRL3-GMCL1 mediates 53BP1 degradation, promoting evasion from mitotic surveillance upon paclitaxel treatment

ABSTRACT: The Mitotic Surveillance Pathway (MSP) is a critical quality control mechanism that monitors mitosis duration. Prolonged mitosis - caused by genomic defects, spindle errors, or anti-mitotic drugs such as paclitaxel - induces formation of the ternary -mitotic stopwatch- complex composed of 53BP1, USP28, and p53. This complex protects p53 from MDM2-mediated degradation, and its accumulation transmits a memory of the delayed mitosis to the daughter cells, where p53 signaling triggers cell cycle arrest and apoptosis. In Paclitaxel-resistant cancers, cells bypass the MSP, enabling unchecked proliferation and survival, though the underlying mechanisms remain unknown. Here, we identify CRL3GMCL1 as the ubiquitin ligase that targets 53BP1 for degradation during prolonged M phase. In cancers with high GMCL1 levels, the CRL3GMCL1-mediated degradation of 53BP1 prevents the formation of the mitotic stopwatch complex, leading to p53 degradation and sustained proliferation. Loss of GMCL1 stabilizes mitotic 53BP1 levels and restores paclitaxel sensitivity. Our results indicate that combining GMCL1 inhibition with taxane treatment represent a novel strategy to restore taxane sensitivity in cancers. The mass spectrometric data files for the protein complex analysis of FLAG-tagged: (i) wild-type GMCL1 (GMCL1 WT), (ii) a GMCL1 E142K mutant (GMCL1 EK for short), which disrupts its ability to bind with CUL3, and (iii) a GMCL1 BTB/BACK-only mutant, which misses GMCL1's putative C-terminal substrate-binding domain are included in this entry.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Beatrix M Ueberheide  

PROVIDER: MSV000097235 | MassIVE | Tue Mar 04 07:57:00 GMT 2025

SECONDARY ACCESSION(S): PXD061458

REPOSITORIES: MassIVE