The RepID–CRL4 ubiquitin ligase complex regulates metaphase to anaphase transition via BUB3 degradation

Sang-Min Jang, Jenny F. Nathans, Haiqing Fu, Christophe E. Redon, Lisa M. Jenkins, Bhushan L. Thakur, Lőrinc S. Pongor, Adrian M. Baris, Jacob M. Gross, Maura J. OʹNeill, Fred E. Indig, Steven D. Cappell and Mirit I. Aladjem ()
Additional contact information
Sang-Min Jang: National Cancer Institute, NIH
Jenny F. Nathans: National Cancer Institute, NIH
Haiqing Fu: National Cancer Institute, NIH
Christophe E. Redon: National Cancer Institute, NIH
Lisa M. Jenkins: National Cancer Institute, NIH
Bhushan L. Thakur: National Cancer Institute, NIH
Lőrinc S. Pongor: National Cancer Institute, NIH
Adrian M. Baris: National Cancer Institute, NIH
Jacob M. Gross: National Cancer Institute, NIH
Maura J. OʹNeill: Frederick National Laboratory for Cancer Research
Fred E. Indig: National Institute on Aging, NIH
Steven D. Cappell: National Cancer Institute, NIH
Mirit I. Aladjem: National Cancer Institute, NIH

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract The spindle assembly checkpoint (SAC) prevents premature chromosome segregation by inactivating the anaphase promoting complex/cyclosome (APC/C) until all chromosomes are properly attached to mitotic spindles. Here we identify a role for Cullin–RING ubiquitin ligase complex 4 (CRL4), known for modulating DNA replication, as a crucial mitotic regulator that triggers the termination of the SAC and enables chromosome segregation. CRL4 is recruited to chromatin by the replication origin binding protein RepID/DCAF14/PHIP. During mitosis, CRL4 dissociates from RepID and replaces it with RB Binding Protein 7 (RBBP7), which ubiquitinates the SAC mediator BUB3 to enable mitotic exit. During interphase, BUB3 is protected from CRL4-mediated degradation by associating with promyelocytic leukemia (PML) nuclear bodies, ensuring its availability upon mitotic onset. Deficiencies in RepID, CRL4 or RBBP7 delay mitotic exit, increase genomic instability and enhance sensitivity to paclitaxel, a microtubule stabilizer and anti-tumor drug.

Date: 2020
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DOI: 10.1038/s41467-019-13808-9

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