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特雷克斯1外核酶降解ssDNA以防止慢性检查点激活和自身免疫性疾病
Yun-Gui Yang1, Tomas Lindahl, Deborah E Barnes
1Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
Cell
|November 30, 2007
概括
特雷克斯1酶缺乏导致免疫系统问题,允许单链DNA积累. 恢复Trex1功能可以预防与DNA损伤相关的自身炎症性疾病.
科学领域:
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
- 遗传学 是一个遗传学.
背景情况:
- 人类TREX1基因的突变导致艾卡迪-古提耶氏综合征,这是一个免疫系统功能障碍的疾病.
- 特雷克斯1是哺乳动物中关键的3'DNA外核酶,对DNA维护至关重要.
- 缺乏Trex1的小鼠表现出一种自身炎症的表型,但潜在的机制尚不清楚.
研究的目的:
- 为了阐明Trex1缺陷自身炎症疾病背后的机制.
- 研究Trex1在DNA损伤反应和免疫激活中的作用.
主要方法:
- 在压力条件下对Trex1的细胞局部化研究 (射,氧尿素).
- 在Trex1缺乏的细胞中分析细胞周期进展 (G1/S过渡).
- 对DNA损伤检查点激活的评估 (取决于ATM).
- 检测单链DNA积累的情况.
主要成果:
- 在DNA损伤后的S阶段,Trex1转移到核中.
- 缺少Trex1的细胞显示G1/S过渡受损和持续的ATM依赖检查点激活.
- 在S阶段产生的持久单链DNA分子,在Trex1缺乏细胞的内质网膜中积聚.
- Trex1处理来自异常复制中间体的单链DNA.
结论:
- 特雷克斯1对于处理由复制应激引起的单链DNA中间体至关重要.
- 对于减弱DNA损伤检查点信号,Trex1活动至关重要.
- 缺陷的Trex1功能导致慢性检查点激活和病态免疫反应.
相关概念视频
Nucleotide Excision Repair
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Nucleotide Excision Repair
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Translesion DNA Polymerases
Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
DNA 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...
Nucleotide Excision Repair
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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...
DNA 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...

