随处可见的Fancd2将Fan1招募到停滞的复制分叉中,以防止基因组的不稳定
Christophe Lachaud1, Alberto Moreno2, Francesco Marchesi3
1Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Science (New York, N.Y.)
|January 23, 2016
概括
通过无处不在的Fancd2招募Fan1核酶对于基因组稳定性至关重要. 这种过程可以防止DNA复制分叉停滞期间的染色体异常,即使没有DNA跨链,Fan1变异也会导致易患癌症的表型.
科学领域:
- 分子生物学
- 遗传学
- 癌症研究
背景情况:
- 对于DNA跨链 (ICL) 修复来说,Fancd2的单元化至关重要.
- Fan1核酶被无处不在的Fancd2招募到ICL中,这表明它在ICL修复机制中的作用.
研究的目的:
- 阐明Fancd2在DNA修复和基因组稳定中的Fan1招募的精确作用.
- 研究Fan1在DNA复制分叉进展中的功能及其对染色体完整性的影响.
主要方法:
- 使用基因小鼠模型 (Fan1核酶缺陷的诺金小鼠).
- 在高危胰腺癌患者样本中分析Fan1变异.
- 在各种条件下评估DNA复制分叉动态和染色体稳定性.
主要成果:
- 对于ICL修复本身来说,无处不在的Fancd2对Fan1的招募是没有必要的.
- Fan1活性对于抑制DNA复制分叉进展和防止分叉停滞期间染色体异常至关重要,独立于ICL.
- 患有Fan1核酶缺陷的小鼠对癌症的易感性增加.
- 在胰腺癌中发现的一种Fan1变体破坏了Fancd2的招募,导致基因不稳定,而不会损害ICL的修复.
结论:
- 随处可见的Fancd2的Fan1招募在处理停滞的DNA复制分叉中起着至关重要的作用,这对于保持基因组稳定性和预防癌症至关重要.
- 这些发现突显了Fan1在ICL修复之外的新功能,强调了它在DNA复制压力期间保护基因组完整性的重要性.
相关概念视频
02:37Restarting Stalled Replication Forks
6.5K
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
6.5K
02:37Restarting Stalled Replication Forks
2.5K
2.5K
01:02The DNA Replication Fork
42.9K
An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork. Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication...
42.9K
01:02The DNA Replication Fork
20.2K
20.2K
02:36DNA Damage can Stall the Cell Cycle
10.4K
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...
10.4K
02:36DNA Damage Can Stall the Cell Cycle
3.4K
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...
3.4K