通过复制因子Mcm10稳定可扩展DNA重复,促进细胞活力
Chiara Masnovo1, Zohar Paleiov2, Daniel Dovrat2
1Department of Biology, Tufts University, Medford, MA, 02155, USA.
Nature communications
|December 3, 2024
概括
麦克姆10缺乏导致三核酸重复不稳定性,通过破坏CMG基酶相互作用,导致复制分叉停滞. 这会影响细胞活力和基因组稳定性,特别是当RPA水平较低时.
科学领域:
- 遗传学 遗传学 是一个
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 三核酸重复,比如弗里德里希的衰减 (GAA) n重复,在DNA复制和修复过程中容易发生致病性扩张.
- 复制分叉停滞和重复序列的不稳定性是基因组不稳定的关键因素.
研究的目的:
- 为了研究Mcm10的作用,一个重要的复制体组件,在维持扩展的三核酸重复的稳定性.
- 阐明Mcm10缺乏影响DNA复制和修复在 (GAA) n重复的机制.
主要方法:
- 利用一个芽酵母模型系统来研究 (GAA) n重复不稳定性.
- 使用活细胞显微镜观察复制叉的动态.
- 评估了Mcm10缺乏和RPA水平对细胞活力和重复稳定性的影响.
- 研究了Rad9检查点和DNA聚合酶三角酶在重复扩张中的作用.
主要成果:
- 由于受损的CMG螺旋酶相互作用,Mcm10缺乏显著增加 (GAA) 的重复不稳定性.
- 在Mcm10缺乏细胞中观察到在 (GAA) 100重复时增加的复制分叉停滞.
- 扩大重复的细胞活力取决于Mcm10功能和RPA水平,涉及Rad9检查点激活.
- 不有效的修复,特别是在RPA耗尽的情况下,导致DNA破裂和细胞死亡.
结论:
- 通过具有挑战性的重复区域进行有效复制,CMG-Mcm10相互作用至关重要.
- 在保持基因组稳定性和细胞存活方面,Mcm10通过防止重复扩张和DNA断裂发挥着至关重要的作用.
- 了解Mcm10的功能,可以了解重复扩张障碍的病原性.
相关概念视频
02:37Restarting Stalled Replication Forks
5.7K
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,...
5.7K
02:37DNA Damage can Stall the Cell Cycle
9.0K
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...
9.0K
01:02The DNA Replication Fork
35.5K
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...
35.5K
02:15Replicative Cell Senescence
3.6K
Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
3.6K
02:31Homologous Recombination
50.2K
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...
50.2K
02:23Abnormal Proliferation
4.4K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.4K