BubR1, a spindle assembly checkpoint protein in mammalian oocyte meiosis

时间:2010年04月15日 访问次数:1878

Cell Cycle. 2010 Apr 15;9(8):1458.

Heng-Yu Fan*

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During eukaryote mitosis, spindle assembly checkpoint (SAC) is a ubiquitous surveillance mechanism to ensure genome stability. Through blocking precocious anaphase onset, SAC prevents chromosome mis-segregation and aneuploidy, and its defection is associated with tumorigenesis, early embryo death, spontaneous abortion or genetic diseases. So far, numerous SAC components have been identified in mitosis. Mad1, Mad2, Mad3 (BubR1), Bub1 and Bub3 are regarded as the core components of SAC. Moreover, Mad2, BubR1, Bub3 and CDC20 constitute mitotic checkpoint complex (MCC) which is considered as the direct effector of the SAC pathway.1 The checkpoint proteins are activated and recruited to specific subcellular positions at prometaphase to avoid precocious separation of sister chromatids during mitotic metaphase.   

Most of the results about SAC components and mechanisms are obtained from mitosis. However, in mammalian meiosis, the SAC functions are not fully understood. Different from mitosis, meiosis undergoes two successive divisions with only one round of DNA replication, thereby producing haploid gametes. It is believed that the surveillance of the separation of chromosomes by SAC pathway in mitosis may exist in the meiosis of mammalian germ cells. Recently, the functions of some core mitotic checkpoint proteins in oocyte meiosis of mouse have been validated. It has been demonstrated that these checkpoint proteins play important roles in surveillance of the fidelity of chromosome segregation at meiosis I and/or meiosis II. The paper by Wei et al. published in the March 15 issue of Cell Cycle describes BubR1 as a checkpoint protein that regulates meiotic maturation in mouse oocyte.

BubR1 is a component of MCC that regulates anaphase onset in mitosis. The checkpoint function of other constituents of MCC has been detected in the mouse oocyte. The studies by Wei et al. about BubR1 checkpoint function provide further evidence for the existence of SAC in oocyte meiosis. They show that BubR1 localizes on kinetochores after germinal vesicle breakdown and at prometaphase stage under physiological condition, which is analogous to that in mitosis. The potential surveillance of BubR1 still exists after it disappears from kinetochores. Misaligned chromosomes at metaphase stage in BubR1-depeleted oocytes and cold treatment assay also indicate that BubR1 is associated with kinetochore-microtubule attachments. They observe that the disturbance of BubR1 expression level induces abnormal oocyte meiotic maturation; furthermore BubR1 is essential for the spindle checkpoint because their studies show BubR1 depletion abolishes meiotic arrest induced by a low dose of nocodazole. In addition,they find germinal vesicle breakdown is accelerated in BubR1-depleted oocytes, which is different from that in mitosis. At the sametime, Homer et al.show that BubR1 regulates first meiotic prophase and then prometaphase progression in mouse oocyte. They show that depletion of BubR1 causes precocious germinal vesicle breakdown, and then arrest before completing MI.

There is increasing evidence that SAC pathway exists in meiosis, and many of its components are conserved between mitosis and meiosis. For examples, phosphorylated Bub1 and Mad2 localize to kinetochores at metaphase I and metaphase II in mouse female meiosis; meanwhile meiotic arrest can be induced by exposure of oocytes to chemicals interfering with microtubule dynamics at meiosis I and meiosis II. But it seems that the components and mechanisms may be different between mitosis and meiosis, even between the meioses of male and female germ cells. In mitosis, BubR1 is a core SAC component with kinase activity, and its functions as a SAC protein, mitotic timer, and spindle regulator are substantially separable. For meiosis in male, it seems that Mad2 and Bub3 are not required, while BubR1 is essential.9For meiosis of oocyte, Mad2, Bub3 and BubR1 are all important at metaphase stage, moreover, BubR1 is also active at prometaphase I stage. In consideration of the differences of mitosis and meiosis, more work needs to be done about SAC in meiosis.