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

• Published in: Nature communications Vol. 11; no. 1; p. 24
• Main Authors: Jang, Sang-Min, Nathans, Jenny F., Fu, Haiqing, Redon, Christophe E., Jenkins, Lisa M., Thakur, Bhushan L., Pongor, Lőrinc S., Baris, Adrian M., Gross, Jacob M., OʹNeill, Maura J., Indig, Fred E., Cappell, Steven D., Aladjem, Mirit I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/31; 13/89; 14/19; 14/63; 631/337/475/2290; 631/80/458/582; 631/80/641/1655; 631/80/641/2002; 631/80/641/2187; 82/29; 82/58; 82/83; Adenomatous polyposis coli; Anaphase; Anaphase-promoting complex; Assembly; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Chromatin; Chromosomes; Cullin; Degradation; Deoxyribonucleic acid; DNA; DNA biosynthesis; Embryos; Genomic instability; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Leukemia; Metaphase; Mitosis; multidisciplinary; Paclitaxel; Poly-ADP-Ribose Binding Proteins - genetics; Poly-ADP-Ribose Binding Proteins - metabolism; Promyelocytic Leukemia Protein - genetics; Promyelocytic Leukemia Protein - metabolism; Promyeloid leukemia; Protein Binding; Proteins; Proteolysis; Replication; Replication origins; Retinoblastoma protein; Retinoblastoma-Binding Protein 7 - genetics; Retinoblastoma-Binding Protein 7 - metabolism; Science; Science (multidisciplinary); Sensitivity enhancement; Spindle Apparatus - metabolism; Spindles; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13808-9

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. The spindle assembly checkpoint (SAC) safeguards chromosome segregation by regulating the anaphase promoting complex/cyclosome (APC/C), allowing chromosomes to correctly attach to mitotic spindles. Here the authors reveal a role for Cullin–RING ubiquitin ligase complex 4 (CRL4) in regulating metaphase to anaphase transition via BUB3 degradation.