The ubiquitin ligase CRL2ZYG11 targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage.
The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase is known to target the degradation of cyclin B1, which is crucial for mitotic progression in animal cells. In this study, we show that the ubiquitin ligase CRL2ZYG-11redundantly targets the degradation of cyclin B1 in Caenorhabditis elegans and human cells. In C. elegans, both CRL2ZYG-11and APC/C are required for proper progression through meiotic divisions. In human cells, inactivation of CRL2ZYG11A/Bhas minimal effects on mitotic progression when APC/C is active. However, when APC/C is inactivated or cyclin B1 is overexpressed, CRL2ZYG11A/B-mediated degradation of cyclin B1 is required for normal progression through metaphase. Mitotic cells arrested by the spindle assembly checkpoint, which inactivates APC/C, often exit mitosis in a process termed "mitotic slippage," which generates tetraploid cells and limits the effectiveness of antimitotic chemotherapy drugs. We show that ZYG11A/B subunit knockdown, or broad cullin-RING ubiquitin ligase inactivation with the small molecule MLN4924, inhibits mitotic slippage in human cells, suggesting the potential for antimitotic combination therapy.
Department of Cellular Biology, University of Georgia, Athens, GA 30602.
Riju S
http://orcid.org/0000-0002-2225-8729
RS
Balachandran
Department of Genetics, University of Georgia, Athens, GA 30602.
Cassandra S
http://orcid.org/0000-0003-2764-8563
CS
Heighington
Department of Cellular Biology, University of Georgia, Athens, GA 30602.
Natalia G
http://orcid.org/0000-0003-2688-6009
NG
Starostina
Department of Cellular Biology, University of Georgia, Athens, GA 30602.
James W
http://orcid.org/0000-0001-9118-4789
JW
Anderson
Department of Cellular Biology, University of Georgia, Athens, GA 30602.
David L
http://orcid.org/0000-0002-1099-0605
DL
Owen
Department of Cellular Biology, University of Georgia, Athens, GA 30602.
Srividya
http://orcid.org/0000-0002-5930-2033
S
Vasudevan
Department of Cellular Biology, University of Georgia, Athens, GA 30602 ekipreos@uga.edu.
Edward T
http://orcid.org/0000-0001-9650-3558
ET
Kipreos
D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D059008:Time-Lapse Imaging
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D056744:Cyclin B1; C454941:ZYG11A protein, human; C454942:zyg-11 protein, C elegans; D064173:Anaphase-Promoting Complex-Cyclosome; D016203:CDC2 Protein Kinase; D015739:Nocodazole