Regulation of mitotic inhibitor Mik1 helps to enforce the DNA damage checkpoint.
Regulation of mitotic inhibitor Mik1 helps to enforce the DNA damage checkpoint.
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DOI：
10.1091/mbc.11.1.1
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发表时间：
2000-01
影响因子：
3.3
通讯作者：
Russell P
中科院分区：
文献类型：
--
作者：
Baber-Furnari BA;Rhind N;Boddy MN;Shanahan P;Lopez-Girona A;Russell P
蛋白激酶Chk1加强DNA损伤检查点。这个检查点延迟有丝分裂，直到受损的DNA被修复。Chk1调节Cdc25的活性和定位，Cdc25是激活cdk的酪氨酸磷酸酶Cdc2。在这里，我们报告了Mik1，一种抑制Cdc2的酪氨酸激酶，受到DNA损伤检查点的正调节。在缺乏Cdc25的菌株中，Mik1是检查点反应所必需的。长期DNA损伤检查点阻滞在Δmik1细胞中失败。DNA损伤以依赖chk1的方式增加Mik1丰度。泛素化的Mik1在蛋白酶体突变体中积累，这表明Mik1通常具有短的半衰期。因此，DNA损伤检查点可能调节Mik1的降解。在未受干扰的细胞周期中，Mik1蛋白和mRNA振荡，在S期左右检测到峰值。这些数据表明，Mik1丰度的调控有助于将有丝分裂的开始与DNA复制和修复的完成结合起来。Cdc25的协同负调控和Mik1的协同正调控确保了DNA损伤检查点的有效运行。
The protein kinase Chk1 enforces the DNA damage checkpoint. This checkpoint delays mitosis until damaged DNA is repaired. Chk1 regulates the activity and localization of Cdc25, the tyrosine phosphatase that activates the cdk Cdc2. Here we report that Mik1, a tyrosine kinase that inhibits Cdc2, is positively regulated by the DNA damage checkpoint. Mik1 is required for checkpoint response in strains that lack Cdc25. Long-term DNA damage checkpoint arrest fails in Δmik1 cells. DNA damage increases Mik1 abundance in a Chk1-dependent manner. Ubiquitinated Mik1 accumulates in a proteasome mutant, which indicates that Mik1 normally has a short half-life. Thus, the DNA damage checkpoint might regulate Mik1 degradation. Mik1 protein and mRNA oscillate during the unperturbed cell cycle, with peak amounts detected around S phase. These data indicate that regulation of Mik1 abundance helps to couple mitotic onset to the completion of DNA replication and repair. Coordinated negative regulation of Cdc25 and positive regulation of Mik1 ensure the effective operation of the DNA damage checkpoint.