DDX39A解决了复制分叉关联的RNA-DNA混合体,以平衡分叉保护和裂变,以维持基因组稳定性
Zhanzhan Xu1, Chen Nie1, Junwei Liao1
1Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing 100191, China.
Molecular cell
|December 20, 2024
概括
复制叉关联的RNA-DNA混合体 (RF-RDs) 保护活跃基因中的DNA复制. DDX39A解决了这些混合物重新启动叉,提供了新的癌症治疗目标.
科学领域:
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
- 细胞生物学 细胞生物学
背景情况:
- 复制叉的稳定性对于DNA复制忠实性和预防突变至关重要,特别是在转录活跃的基因组区域.
- 复制压力可能导致叉子崩和基因组不稳定.
- 越来越多的RNA-DNA混合体 (RF-RDs) 被认为是具有不同细胞作用的重要核酸结构.
研究的目的:
- 在人类细胞中研究复制叉相关RNA-DNA混合体 (RF-RDs) 的存在和功能.
- 在停滞的复制分叉中识别参与RF-RD分辨率的蛋白质.
- 探索向RF-RDs在癌症治疗中的治疗潜力.
主要方法:
- 细胞测试用于检测和可视化复制分叉中的RF-RD.
- 生物化学方法用于识别与停滞叉和RF-RDs的蛋白质相互作用.
- 基因操纵研究RF-RDs溶解对复制叉稳定性和DNA修复的影响.
主要成果:
- 在人类细胞的转录活性区域的复制分叉中,RF-RDs很普遍.
- 这些杂交物防止DNA2对新生DNA的降解,并在复制应激过程中防止复制叉的崩.
- 一种RAD51相关蛋白质DDX39A结合了停滞的叉子并解决了RF-RDs,促进了DNA切除和叉子重新启动.
- 不调节RF-RD溶解导致复制的崩或增加稳定性,影响基因组的不稳定性和化学抵抗.
结论:
- 在转录活跃的基因组区域内,RF-RD在维持复制分叉稳定性方面发挥着至关重要的作用.
- DDX39A通过解决RF-RDs来促进复制叉重新启动,突出其在DNA复制中的重要性.
- 针对RF-RDs是一个有希望的策略,通过克服化学抵抗来提高化疗剂的疗效.
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
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
02:31Homologous 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
02:04Fixing Double-strand Breaks
12.2K
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...
12.2K
01:20Mismatch Repair
4.8K
Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
4.8K
01:29Replication in Eukaryotes
13.1K
In eukaryotic cells, DNA replication is highly conserved and tightly regulated. Multiple linear chromosomes must be duplicated with high fidelity before cell division, so there are many proteins that fulfill specialized roles in the replication process. Replication occurs in three phases: initiation, elongation, and termination, and ends with two complete sets of chromosomes in the nucleus.
Many Proteins Orchestrate Replication at the Origin
Eukaryotic replication follows many of the same...
Many Proteins Orchestrate Replication at the Origin
Eukaryotic replication follows many of the same...
13.1K