通过ATR介导的层A/C的酸化,DNA损伤诱导核外破裂
Marton Tibor Kovacs1, Marie Vallette1, Pauline Wiertsema1
1Inserm U830, PSL Research University, Institut Curie, 75005 Paris, France.
Molecular cell
|October 13, 2023
概括
通过ATR激活和层层A/C酸化,DNA损伤会触发核外 (NE) 破裂. 具有DNA修复缺陷的癌细胞中的这种NE脆弱性提供了一个新的治疗策略.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 核包裹 (NE) 完整性对于核稳定性至关重要.
- 在癌细胞中观察到NE破裂,特别是在机械应力下.
- 独立于机械应力的自发NE破裂机制尚未得到充分理解.
研究的目的:
- 为了阐明自发核膜破裂背后的分子机制.
- 调查DNA损伤和ATR信号在NE破裂中的作用.
- 探索针对癌细胞中NE脆弱性的治疗潜力.
主要方法:
- 研究了DNA损伤对核外完整性的影响.
- 使用生物化学测试来评估层层A/C酸化.
- 检查了不同DNA修复能力的癌细胞中NE破裂的频率.
主要成果:
- 通过ATR依赖的酸化层A/C,DNA损伤会诱导核膜破裂.
- 酸化后变化的薄膜组件有助于NE破裂.
- 患有DNA修复缺陷的癌细胞表现出DNA损伤诱导的NE破裂和对NE扰动的敏感性增加.
结论:
- DNA损伤是自发核外破裂的直接触发因素.
- 通过ATR介导的层状A/C酸化是NE破裂的关键分子事件.
- 准NE脆弱性是一个有希望的策略,可以提高DNA修复缺陷癌症的化疗疗效率.
相关概念视频
DNA Damage can Stall the Cell Cycle
9.2K
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...
9.2K
Disassembly of Intermediate Filaments
2.1K
Intermediate filaments (IFs) do not undergo spontaneous disassembly. Enzymes, kinases, and phosphatases add and remove phosphates from specific sites to regulate their disassembly. The IF concentration in the cytoplasm also regulates the disassembly. If the concentration crosses a threshold, it activates the protein kinases in the vicinity, allowing the phosphorylation of IFs.
Keratin proteins, found at the cell periphery near cell junctions, undergo a cycle of assembly and disassembly. In Type...
Keratin proteins, found at the cell periphery near cell junctions, undergo a cycle of assembly and disassembly. In Type...
2.1K
Restarting Stalled Replication Forks
5.8K
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,...
5.8K
Nucleotide Excision Repair
37.1K
Overview
37.1K
Homologous Recombination
50.6K
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...
50.6K
The Intrinsic Apoptotic Pathway
6.6K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.6K


