独特的Pt(II) 诱导的核细胞应激反应及其偏离DNA损伤反应途径
Hannah C Pigg1, Katelyn R Alley1, Christopher R Griffin1
1Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon, USA.
The Journal of biological chemistry
|October 7, 2024
概括
化合物,如氧沙,通过核应激诱导细胞死亡,独立于DNA损伤反应 (DDR). 这种压力与G1细胞周期阶段有关,并且是不可逆转的,与其他一些核应激因素不同.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 药理学 药理学是指药理学的学科.
背景情况:
- 基于的化疗药物西斯和氧沙的精确作用机制仍然不完全理解.
- 虽然已知西斯丁通过DNA损伤反应 (DDR) 触发细胞死亡,但氧沙丁越来越多地与明显的核应激途径有关.
- 现有的研究已经确定了 (Pt) 化合物的结构特征,这些化合物可以诱导核应激,但核应激和DDR之间的相互作用尚不清楚.
研究的目的:
- 研究Pt(II) 衍生物诱导的核子应激和DNA损伤反应 (DDR) 之间的关系.
- 阐明Pt(II) 诱导的核子应激所涉及的特定条件和细胞周期阶段.
- 为了比较Pt(II) 诱导的核子应激特征与其他小分子化合物诱导的核子应激特征.
主要方法:
- 研究了Pt(II) 衍生物,因为它们具有诱导核应激的能力.
- 检查了核应激诱导和DDR通路之间的相关性,包括ATM/ATR.
- 评估了细胞周期阶段 (特别是G1/S检查点) 对Pt(II) 诱导的核应激的影响.
- 比较Pt(II) 诱导的核子应激与由阿基诺米辛D,BMH-21和CX-5461引起的核子应激.
主要成果:
- 诱导Pt (II) 的核子应激发生在独立于ATM/ATR依赖的DDR通路时,并且在DDR被抑制时被观察到.
- Pt(II) 诱导的核子应激似乎与 G1 细胞周期阶段有关,正如 cisplatin 在 G1/S 检查点的作用所证明的那样.
- Pt(II) 化合物诱导不可逆转的核应激,与与其他小分子核应激剂观察到的可变可逆性形成鲜明对比.
结论:
- 由Pt (II) 诱导的核子应力代表了一个独立的路径,它独立于标准的ATM/ATR依赖的DDR运行.
- 细胞周期的G1阶段可能在调解Pt(II) 化合物对核应激的影响方面发挥关键作用.
- 了解Pt(II) 诱导的核子应激的独特,不可逆转的性质,为基于的化疗机制和潜在的治疗策略提供了新的见解.
相关概念视频
DNA Damage can Stall the Cell Cycle
9.1K
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...
9.1K
Nucleotide Excision Repair
3.5K
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
3.5K
DNA Damage Can Stall the Cell Cycle
2.6K
2.6K
Nucleosome Remodeling
9.0K
Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
9.0K
Translesion DNA Polymerases
9.9K
Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
9.9K
Overview of DNA Repair
30.9K
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...
30.9K


