...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Cell cycle >Reduced kinase activity of polo kinase Cdc5 affects chromosome stability and DNA damage response in S-cerevisiae
【24h】

Reduced kinase activity of polo kinase Cdc5 affects chromosome stability and DNA damage response in S-cerevisiae

机译：马球激酶Cdc5的激酶活性降低影响S-酿酒酵母中的染色体稳定性和DNA损伤反应

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Polo-like kinases (PLKs) control several aspects of eukaryotic cell division and DNA damage response. Remarkably, PLKs are overexpressed in several types of cancer, being therefore a marker of bad prognosis. As such, specific PLK kinase activity inhibitors are already used in clinical trials and the regulation of PLK activation is a relevant topic of cancer research. Phosphorylation of threonine residues in the T-loop of the kinase domain is pivotal for PLKs activation. Here, we show that T238A substitution in the T-loop reduces the kinase activity of Cdc5, the only PLK in Saccharomyces cerevisiae, with minor effect on cell growth in unperturbed conditions. However, the cdc5-T238A cells have increased rate of chromosome loss and gross chromosomal rearrangements, indicating altered genome stability. Moreover, the T238A mutation affects timely localization of Cdc5 to the spindle pole bodies and blocks cell cycle restart after one irreparable double-strand break. In cells responding to alkylating agent metylmethane sulfonate (MMS), the cdc5-T238A mutation reduces the phosphorylation of Mus81-Mms4 resolvase and exacerbates the MMS sensitivity of sgs1 cells that accumulate Holliday junctions. Of importance, the previously described checkpoint adaptation defective allele, cdc5-ad does not show reduced kinase activity, defective Mms4 phosphorylation and genetic interaction with sgs1. Our data define the importance of regulating Cdc5 activity through T-loop phosphorylation to preserve genome integrity and respond to DNA damage.
机译：Polo样激酶（PLK）控制真核细胞分裂和DNA损伤反应的多个方面。值得注意的是，PLKs在几种类型的癌症中过表达，因此是不良预后的标志。因此，特定的PLK激酶活性抑制剂已经在临床试验中使用，而PLK活化的调控是癌症研究的一个相关主题。激酶结构域T环中苏氨酸残基的磷酸化对于PLK激活至关重要。在这里，我们显示T环中的T238A取代降低了酿酒酵母中唯一的PLK Cdc5的激酶活性，在不受干扰的条件下对细胞生长的影响很小。但是，cdc5-T238A细胞的染色体丢失率和总体染色体重排率增加，表明基因组稳定性发生了变化。此外，T238A突变会影响Cdc5到纺锤极体的及时定位，并阻止一次不可修复的双链断裂后细胞周期的重启。在响应烷基化剂甲基甲烷磺酸盐（MMS）的细胞中，cdc5-T238A突变降低了Mus81-Mms4溶解酶的磷酸化，并加剧了积累霍利迪结的sgs1细胞的MMS敏感性。重要的是，先前描述的检查点适应缺陷等位基因cdc5-ad并未显示激酶活性降低，Mms4磷酸化缺陷以及与sgs1的遗传相互作用。我们的数据定义了通过T环磷酸化调节Cdc5活性以保持基因组完整性和应对DNA损伤的重要性。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号