Yeast ORC sumoylation status fine-tunes origin licensing.
Yeast ORC sumoylation status fine-tunes origin licensing.
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酵母ORC sumoylation状态微调原产地许可。
DOI：
10.1101/gad.349610.122
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发表时间：
2022-08-04
影响因子：
10.5
通讯作者：
Zhao, Xiaolan
中科院分区：
文献类型：
--
作者：
Regan-Mochrie, Gemma;Hoggard, Timothy;Bhagwat, Nikhil;Lynch, Gerard;Hunter, Neil;Remus, Dirk;Fox, Catherine A.;Zhao, Xiaolan
在这里，Regan-Mochrie等人试图了解ORC类小泛素化的生物学后果，并且他们使用多种方法报告了酵母ORC的高类小泛素化和低类小泛素化对ORC功能和起源活性的影响。他们的研究结果表明，必须适当控制酵母ORC sumoylation状态，以实现整个基因组的最佳起源活性和基因组稳定性。类小泛素化是一种重要的翻译后修饰，对调节染色体的复制和稳定性非常重要。通过将MCM复制解旋酶加载到起始点上来指导DNA复制起始的起始点识别复合物（ORC）在酵母和人细胞中均被苏莫酰化。然而，ORC类小泛素化的生物学后果尚不清楚。在这里，我们报告了酵母ORC的hypersumoylation和hyposumoylation对ORC活性和起源功能的影响，使用多种方法。ORC hypersumoylation优先降低了早期起源的一个子集的功能，而Orc 2 hyposumoylation有相反的效果。从机制上讲，ORC过sumoylation减少了MCM在体外的负载，并减少了MCM在体内的染色质缔合。ORC的高sumoylation或低sumoylation导致基因组的不稳定性和酵母对其他基因组维持因子的依赖性，提供了适当的ORC sumoylation水平对细胞适应性很重要的证据。因此，必须适当控制酵母ORC类小泛素化状态以实现跨基因组的最佳起源功能和基因组稳定性。
Here, Regan-Mochrie et al. sought to understand the biological consequences of ORC sumoylation, and they report the effects of hypersumoylation and hyposumoylation of yeast ORC on ORC function and origin activity using multiple approaches. Their findings show that yeast ORC sumoylation status must be properly controlled to achieve optimal origin activity across the genome and genome stability. Sumoylation is emerging as a posttranslation modification important for regulating chromosome duplication and stability. The origin recognition complex (ORC) that directs DNA replication initiation by loading the MCM replicative helicase onto origins is sumoylated in both yeast and human cells. However, the biological consequences of ORC sumoylation are unclear. Here we report the effects of hypersumoylation and hyposumoylation of yeast ORC on ORC activity and origin function using multiple approaches. ORC hypersumoylation preferentially reduced the function of a subset of early origins, while Orc2 hyposumoylation had an opposing effect. Mechanistically, ORC hypersumoylation reduced MCM loading in vitro and diminished MCM chromatin association in vivo. Either hypersumoylation or hyposumoylation of ORC resulted in genome instability and the dependence of yeast on other genome maintenance factors, providing evidence that appropriate ORC sumoylation levels are important for cell fitness. Thus, yeast ORC sumoylation status must be properly controlled to achieve optimal origin function across the genome and genome stability.
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