Abstract
AbstractFaithful chromosome segregation and thereby accurate gene transmission are crucial for all organisms. Until proper attachment of the mitotic spindle to the kinetochore is established, the ubiquitin ligase (E3) Cdc20-activated APC/C (anaphase promoting complex/cyclosome) is repressed by the spindle assembly checkpoint (SAC) and sister chromatin cohesion is protected. Mutants defective in SAC fail to arrest at metaphase even in the presence of damaged microtubules. Interestingly, a similar phenomenon occurs in yeast cells defective in Bub2, a negative factor of the mitotic exit network (MEN), which is required for telophase onset, although its precise molecular mechanism is unknown. Here, we show that chromosome missegregation occurs frequently in bub2&x2206; cells in the presence of damaged microtubules. The loss of Bub2 caused precocious activation of APC/C-Cdh1/Hct1 at pre-anaphase, leading to securin degradation and then separase-mediated cohesin cleavage. Overexpression of CDH1 and CDC14, encoding Cdc14 phosphatase, at pre-anaphase similarly caused chromosome missegregation. Thus, sequential activation of APC/C-Cdc20 and then APC/C-Cdh1 is critical for precise chromosome segregation and precocious activation of APC/C-Cdh1 at pre-anaphase causes genomic instability. Since degradation of human securin is also mediated by APC/C-Cdc20 and APC/C-Cdh1, this study predicts that precocious activation APC/C-Cdh1 in human cells similarly causes genomic instability, and thereby cell death or tumorigenesis.
Highlights
Faculty of Science, Shizuoka University, Shizuoka University, Shizuoka 422-8529, Japan, Running title: Precocious Cdh[1] activation causes genomic instability
A similar phenomenon occurs in yeast cells defective in Bub[2], a negative factor of the mitotic exit network (MEN), which is required for telophase onset 2-5, its precise molecular mechanism is unknown
Since degradation of human securin is mediated by APC/C-Cdc[20] and APC/C-Cdh[1], this study predicts that precocious activation APC/C-Cdh[1] in human cells causes genomic instability, and thereby cell death or tumorigenesis
Summary
Faculty of Science, Shizuoka University, Shizuoka University, Shizuoka 422-8529, Japan, Running title: Precocious Cdh[1] activation causes genomic instability. The loss of Bub[2] caused precocious activation of APC/C-Cdh1/Hct[1] at pre-anaphase, leading to securin degradation and separase-mediated cohesin cleavage. Sequential activation of APC/C-Cdc[20] and APC/C-Cdh[1] is critical for precise chromosome segregation and precocious activation of APC/C-Cdh[1] at pre-anaphase causes genomic instability.
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