Inhibition of CDK7 bypasses spindle assembly checkpoint via premature cyclin B degradation during oocyte meiosis.
To ensure accurate chromosome segregation, the spindle assembly checkpoint (SAC) delays anaphase onset by preventing the premature activation of anaphase-promoting complex/cyclosome (APC/C) until all kinetochores are attached to the spindle. Although an escape from mitosis in the presence of unsatisfied SAC has been shown in several cancer cells, it has not been reported in oocyte meiosis. Here, we show that CDK7 activity is required to prevent a bypass of SAC during meiosis I in mouse oocytes. Inhibition of CDK7 using THZ1 accelerated the first meiosis, leading to chromosome misalignment, lag of chromosomes during chromosome segregation, and a high incidence of aneuploidy. Notably, this acceleration occurred in the presence of SAC proteins including Mad2 and Bub3 at the kinetochores. However, inhibition of APC/C-mediated cyclin B degradation blocked the THZ1-induced premature polar body extrusion. Moreover, chromosomal defects mediated by THZ1 were rescued when anaphase onset was delayed. Collectively, our results show that CDK7 activity is required to prevent premature anaphase onset by suppressing the bypass of SAC, thus ensuring chromosome alignment and proper segregation. These findings reveal new roles of CDK7 in the regulation of meiosis in mammalian oocytes.
Department of Animal Sciences, Chungbuk National University, Cheongju, Republic of Korea.
HaiYang
H
Wang
Department of Animal Sciences, Chungbuk National University, Cheongju, Republic of Korea.
Yu-Jin
YJ
Jo
Department of Animal Sciences, Chungbuk National University, Cheongju, Republic of Korea.
Tian-Yi
TY
Sun
Department of Animal Sciences, Chungbuk National University, Cheongju, Republic of Korea.
Suk
S
Namgoong
Department of Animal Sciences, Chungbuk National University, Cheongju, Republic of Korea.
Xiang-Shun
XS
Cui
Department of Genetic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea. Electronic address: ohjs@skku.edu.
Jeong Su
JS
Oh
Department of Animal Sciences, Chungbuk National University, Cheongju, Republic of Korea. Electronic address: nhkim@chungbuk.ac.kr.
Nam-Hyung
NH
Kim
D000782:Aneuploidy; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D020090:Chromosome Segregation / Q000187:drug effects*; D019926:Cyclin B / Q000235:genetics* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D018386:Kinetochores / Q000378:metabolism / Q000648:ultrastructure; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism; D008540:Meiosis / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009865:Oocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology; D059705:Polar Bodies / Q000378:metabolism / Q000648:ultrastructure; D000075223:Poly-ADP-Ribose Binding Proteins; D061251:Primary Cell Culture; D059748:Proteolysis / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism / Q000648:ultrastructure
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D019926:Cyclin B; D018844:Cyclin-Dependent Kinases; D064246:Mad2 Proteins; D010655:Phenylenediamines; D000075223:Poly-ADP-Ribose Binding Proteins; D011743:Pyrimidines; C489445:Bub3 protein, mouse; C577698:Mad2l1 protein, mouse; C000596184:THZ1 compound; C090586:Cdk7 protein, mouse
APC/C; Aneuploidy; CDK7; Meiosis; Oocyte; Sac