53BP1和LINC复合促进微管依赖的DSB移动性和DNA修复
Francisca Lottersberger1, Roos Anna Karssemeijer1, Nadya Dimitrova1
1Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell
|November 7, 2015
概括
DNA双链断裂 (DSB) 的移动性由53BP1,LINC复合体和微管所调节. 这种移动性有助于健康细胞的DNA修复,但当DNA损伤严重时可能会导致错误.
科学领域:
- 分子生物学
- 细胞生物学
- 遗传学
背景情况:
- 观察到双链断裂 (DSB) 周围的染色质流动性增加,但其在DNA修复中的机制和作用尚未完全理解.
- 了解DSB移动性的因素和后果对于理解DNA修复忠实性和细胞对基因毒性压力的反应至关重要.
研究的目的:
- 通过使用高分辨率活细胞成像系统,阐明DSB中染色体移动性的分子机制.
- 调查DSB移动性对DNA修复过程的功能性贡献,包括非同类末端连接 (NHEJ) 和其潜在的有害影响.
主要方法:
- 使用基于端粒的系统来高分辨率追踪活细胞中的DNA损伤焦点.
- 研究了关键蛋白质 (53BP1,SUN1/2,Nesprin-4) 和细胞结构 (LINC复合体,微管) 在调节DSB移动性的作用.
- 在端粒和辐射诱导的DSB中检查了DSB的移动性,包括在BRCA1缺乏细胞中.
主要成果:
- 对于DSB染色体的移动性,需要53BP1,LINC复合体 (SUN1/2) 和动态微管.
- 这种移动性促进了功能障碍的端粒的非同类结合,Nesprin-4和kinesins参与了端粒融合.
- 53BP1/LINC/微管依赖性可导致BRCA1缺陷细胞中DNA损伤的错误连接,突显其在高损伤情景中的有害作用.
结论:
- 在生理条件下 (少数病变) 进行有效的DNA修复,DSB的移动性是一个受管制的过程.
- 然而,这种移动性可能是有害的,导致具有广泛DNA损伤的细胞 (例如BRCA1缺乏细胞) 的修复错误.
- 这些发现揭示了DSB在维持基因组稳定性方面的双重作用,这取决于细胞环境和DNA损伤的程度.
相关概念视频
02:04Fixing Double-strand Breaks
16.2K
The double-stranded structure of DNA has two major advantages. First, it serves as a safe repository of genetic information where one strand serves as the back-up in case the other strand is damaged. Second, the double-helical structure can be wrapped around proteins called histones to form nucleosomes, which can then be tightly wound to form chromosomes. This way, DNA chains up to 2 inches long can be contained within microscopic structures in a cell. A double-stranded break not only damages...
16.2K
02:04Fixing Double-strand Breaks
4.7K
4.7K
02:31Homologous Recombination
65.5K
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...
65.5K
01:02Long-patch Base Excision Repair
8.3K
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
8.3K
02:37Restarting Stalled Replication Forks
6.6K
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,...
6.6K
01:54Base Excision Repair
27.9K
One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
The first step of...
The first step of...
27.9K