通过RNF8泛素合酶对DNA损伤反应的编排
Nadine K Kolas1, J Ross Chapman, Shinichiro Nakada
1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G1X5, Ontario, Canada.
Science (New York, N.Y.)
|November 17, 2007
概括
无素酶RNF8对于DNA双链断裂修复至关重要,它调解了53BP1和BRCA1.1等关键蛋白质的招募. 这一过程涉及MDC1的ATM-激酶依赖酸化,调节DNA损伤反应.
科学领域:
- 细胞生物学 细胞生物学
- 分子瘤学分子瘤学
- DNA 修复机制的修复机制
背景情况:
- 细胞激活复杂的信号通路,以响应DNA双链断裂 (DSB).
- 像MDC1,53BP1和BRCA1这样的关键蛋白质被招募到DNA损伤部位.
- 正在调查启动这种招募的精确分子机制.
研究的目的:
- 阐明在DNA损伤反应中泛素酶RNF8的作用.
- 研究MDC1,RNF8和ATM在DSB修复中的相互作用.
- 确定RNF8活动对DNA损伤检查点和细胞存活的功能后果.
主要方法:
- 利用技术研究蛋白质相互作用和DNA损伤部位的局部化.
- 采用基因枯竭策略 (例如,UBC13枯竭) 来评估功能影响.
- 评估细胞反应,包括DNA损伤检查点激活和辐射抵抗.
主要成果:
- RNF8调解了53BP1和BRCA1对DNA损伤的招募所必不可少的乌比奎丁结合.
- MDC1通过涉及ATM-酸化基因的依相互作用来招募RNF8.
- E2酶UBC13的耗尽会影响53BP1的招募,这表明它与RNF8.8合作.
- RNF8促进了G2/MDNA损伤检查点,并增强了对电离辐射的抵抗力.
结论:
- 基于ATM的MDC1酸化和RNF8介导的全方位化对于调节DNA损伤反应至关重要.
- RNF8作为一个中央调解器,将上游信号 (ATM-MDC1) 与下游效应器招募 (53BP1,BRCA1) 联系起来.
- 这一途径对于维持基因组稳定性和在DNA损伤后的细胞存活至关重要.
相关概念视频
01:08Nucleotide Excision Repair
Overview
01:38Nucleotide Excision Repair
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
01:08Nucleotide Excision Repair
Overview
02:31Homologous Recombination
The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
02:36DNA Damage can Stall the Cell Cycle
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...
02:36DNA Damage Can Stall the Cell Cycle
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...