The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains
The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains
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DOI：
10.1038/sj.onc.1206831
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发表时间：
2003-10-16
期刊：
影响因子：
8
通讯作者：
Halazonetis, TD
中科院分区：
文献类型：
--
作者：
Bothos, J;Summers, MK;Halazonetis, TD
我们最近描述了一种新的检查点途径，该途径在有丝分裂早期起作用，以延迟响应微管毒物的染色体凝聚。到目前为止，唯一涉及这个检查点途径的基因是chfr，其蛋白产物含有一个环结构域，并且在体外具有泛素连接酶活性。这种活性在体内的意义尚不清楚。最近的一份报告表明，Chfr蛋白通过自身泛素化作用在有丝分裂细胞中靶向蛋白酶体依赖性降解。然而，我们观察到，在有丝分裂中，Chfr表现出磷酸化依赖的电泳迁移，而总体蛋白质水平没有变化。进一步分析其泛素连接酶活性发现Chfr可以催化非典型lys63连接的多泛素链，其中Ubc13-Mms2作为泛素偶联酶。Ubc13-Mms2和lys63 -多泛素链与蛋白酶体靶向蛋白无关，而与细胞应激信号有关。我们提出Chfr可能在微管毒物诱导的有丝分裂应激信号中起作用。
We recently described a novel checkpoint pathway that functions early in mitosis to delay chromosome condensation in response to microtubule poisons. The only gene implicated so far in this checkpoint pathway is chfr, whose protein product contains a RING domain and has ubiquitin ligase activity in vitro. The significance of this activity in vivo is unclear. A recent report suggested that the Chfr protein targets itself for proteasome-dependent degradation in mitotic cells through autoubiquitination. However, we observe that in mitosis Chfr exhibits a phosphorylation-dependent electrophoretic mobility shift with no change in overall protein levels. Further analysis of its ubiquitin ligase activity revealed that Chfr can catalyse the formation of noncanonical Lys63-linked polyubiquitin chains with Ubc13-Mms2 acting as the ubiquitin-conjugating enzyme. Ubc13-Mms2 and Lys63-polyubiquitin chains are not associated with targeting proteins to the proteasome, but rather with signaling cellular stress. We propose that Chfr may have a role in signaling the presence of mitotic stress induced by microtubule poisons.