MDC1是哺乳动物DNA损伤检查点的调解者
Grant S Stewart1, Bin Wang, Colin R Bignell
1Verna & Mars McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature
|February 28, 2003
概括
DNA损伤检查点蛋白1 (MDC1) 的调解者是一种新型蛋白质,与H2AX一起工作,将DNA修复蛋白招募到损伤部位. MDC1对于DNA损伤诱导的细胞循环停止检查点至关重要.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 遗传学 是一个遗传学.
背景情况:
- 细胞拥有复杂的DNA损伤反应网络,包括检查点,以管理DNA复制,细胞循环停止和修复.
- 基因组H2A变体H2AX在招募DNA修复蛋白到DNA损伤部位方面发挥着特定的作用.
研究的目的:
- 为了识别和表征一种参与DNA损伤反应途径的新型蛋白质.
- 阐明这种新蛋白在协调DNA修复和细胞循环检查点激活中的作用.
主要方法:
- 鉴定了一种新型蛋白质MDC1 (DNA损伤检查点蛋白1的介质),具有BRCT和FHA域.
- 在暴露于电离辐射后,对MDC1和玛-H2AX焦点形成的同定位研究.
- 分析MDC1与酸化H2AX的相互作用.
- siRNA介导MDC1的淘汰,以评估其在DNA修复和细胞循环检查点中的功能.
- 研究MDC1在53BP1,BRCA1和MRN焦点的形成和Chk1.1调节中的作用.
主要成果:
- MDC1形成的焦点广泛与玛-H2AX焦点共定位后电离辐射.
- H2AX对于MDC1焦点的形成至关重要,MDC1以酸化依赖的方式与酸化的H2AX相互作用.
- 缺乏MDC1的细胞对电离辐射敏感,损伤引起的焦点 (53BP1,BRCA1,MRN) 的形成受损,部分原因是H2AX酸化减少.
- 缺乏MDC1的细胞无法正确激活细胞周期内S和G2/M检查点,并表现出Chk1.1的失调.
结论:
- MDC1是DNA损伤反应的关键调解者,与H2AX.一起工作.
- MDC1在招募DNA修复蛋白和在DNA损伤后建立细胞循环检查点方面发挥着关键作用.
- MDC1对于正确转导DNA损伤信号至关重要,突出显示其在保持基因组稳定性方面的重要性.
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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
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