ecDNA复制是无组织的,易受复制应激的影响
Jedrzej J Jaworski1, Pauline L Pfuderer2,3, Pawel Czyz4,5
1Division of Protein & Nucleic Acid Chemistry MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.
Nucleic acids research
|July 31, 2025
概括
外染色体DNA (ecDNA) 在癌细胞中异步复制,与染色体DNA不同. 这项研究揭示了ecDNA复制差异,这可能导致针对瘤基因放大的新型癌症疗法.
科学领域:
- 分子生物学分子生物学
- 癌症生物学 癌症生物学
- 遗传学 是一个遗传学.
背景情况:
- 外染色体DNA (ecDNA) 通过瘤基因放大驱动癌症进展,瘤生长,进化和治疗抵抗.
- 对于ecDNA的复制机制尚不清楚,这阻碍了向疗法的开发.
研究的目的:
- 用先进的分子技术研究ecDNA的复制动力学.
- 为了比较ecDNA复制与染色体DNA复制和染色体重整的ecDNA.
主要方法:
- 利用高分辨率的复制时间分析 (Repli-seq) 和DNAscent来测量源点火和复制叉移动.
- 采用基于光激活细胞分类的原生ecDNA (FINE) 隔离方法,在不消化的情况下分离染色化ecDNA.
- 在癌症和控制细胞系中应用大量DNA,分离的ecDNA和染色体重整的ecDNA的方法.
主要成果:
- 证明了COLO 320DM细胞中的ecDNA在整个S阶段表现出异步复制,与染色体DNA不同.
- 观察到重新分配的复制起源,减少复制分叉速度,并增加了ecDNA上的分叉停滞.
- 发现复制应激 (基尿素) 进一步破坏了ecDNA复制,导致改变原始激活和ecDNA枯竭.
结论:
- 与染色体DNA相比,揭示了ecDNA复制动态的根本差异.
- 这些发现为ecDNA在癌症中的作用以及针对瘤基因放大的潜在治疗策略提供了关键的见解.
更多相关视频
相关概念视频
The DNA Replication Fork
36.8K
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...
36.8K
Restarting Stalled Replication Forks
5.9K
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,...
5.9K
DNA Damage can Stall the Cell Cycle
9.3K
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...
9.3K
Homologous Recombination
52.2K
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...
52.2K
Replication in Eukaryotes
14.6K
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...
14.6K
Overview of DNA Repair
31.6K
In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
Chemically...
Chemically...
31.6K


