Drosophila grapes/CHK1 mutants are defective in cyclin proteolysis and coordination of mitotic events
Drosophila grapes/CHK1 mutants are defective in cyclin proteolysis and coordination of mitotic events
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DOI：
10.1016/s0960-9822(99)80399-6
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发表时间：
1999-08-26
期刊：
影响因子：
9.2
通讯作者：
O'Farrell, PH
中科院分区：
文献类型：
--
作者：
Su, TT;Campbell, SD;O'Farrell, PH
果蝇葡萄（grp）基因编码粟酒裂殖酵母Chk 1激酶的同源物，提供细胞周期检查点，延迟有丝分裂以响应DNA复制的抑制[1]。Grp在未受干扰的早期胚胎周期中也是必需的：在缺乏grp的情况下，有丝分裂异常出现在第12周期，染色体在随后的周期中不能完全分离[2，3]。在其他系统中，Chk 1激酶磷酸化并抑制Cdc 25磷酸酶的活性：导致无法从细胞周期蛋白依赖性激酶1（Cdk 1）中去除抑制性磷酸盐，从而阻止进入有丝分裂[4，5]。由于在果蝇胚胎中Cdk 1在第11-13周期中缺乏抑制性磷酸盐[6]，因此尚不清楚Grp/Chk 1的已知作用是否足以在这些周期中发挥作用。我们发现grp的丢失损害了细胞周期蛋白A的蛋白水解，并延迟了姐妹染色体的有丝分裂分离。这些缺陷发生在先前报道的grp表型之前。我们的结论是，Grp激活细胞周期蛋白A降解，并在早期胚胎染色体的分离时间的功能。由于姐妹染色体分离需要细胞周期蛋白A的破坏[7]，GRP促进的细胞周期蛋白破坏的失败也可以解释有丝分裂表型，先前描述的周期12 grp胚胎的有丝分裂失败可能是我们在早期胚胎中描述的表型的更严重形式，我们认为潜在的缺陷是细胞周期蛋白A的降解减少。
The Drosophila grapes (grp) gene, which encodes a homolog of the Schizosaccharomyces pombe Chk1 kinase, provides a cell-cycle checkpoint that delays mitosis in response to inhibition of DNA replication [1]. Grp is also required in the undisturbed early embryonic cycles: in its absence, mitotic abnormalities appear in cycle 12 and chromosomes fail to fully separate in subsequent cycles [2,3]. In other systems, Chk1 kinase phosphorylates and suppresses the activity of Cdc25 phosphatase: the resulting failure to remove inhibitory phosphate from cyclin-dependent kinase 1 (Cdk1) prevents entry into mitosis [4,5]. Because in Drosophila embryos Cdk1 lacks inhibitory phosphate during cycles 11-13 [6], it is not clear that known actions of Grp/Chk1 suffice in these cycles. We found that the loss of grp compromised cyclin A proteolysis and delayed mitotic disjunction of sister chromosomes. These defects occurred before previously reported grp phenotypes. We conclude that Grp activates cyclin A degradation, and functions to time the disjunction of chromosomes in the early embryo. As cyclin A destruction is required for sister chromosome separation [7], a failure in Grp-promoted cyclin destruction can also explain the mitotic phenotype, The mitotic failure described previously for cycle 12 grp embryos might be a more severe form of the phenotypes that we describe in earlier embryos and we suggest that the underlying defect is reduced degradation of cyclin A.