由ZBP1传递的端粒到线粒体信号介导复制性危机
Joe Nassour1, Lucia Gutierrez Aguiar1, Adriana Correia1,2
1The Salk Institute for Biological Studies, La Jolla, CA, USA.
Nature
|February 9, 2023
概括
Z-DNA结合蛋白1 (ZBP1) 调节复制性危机,是一种瘤抑制屏障. 功能障碍的端粒通过线粒体复合体激活ZBP1,引发天生的免疫反应以消除注定致癌的细胞.
科学领域:
- 细胞生物学
- 免疫学
- 癌症研究
背景情况:
- 癌症的发展源于基因/表观遗传变化,
- 复制性危机是一个依赖于自的过程,消除具有不稳定的端粒和染色体问题的细胞.
- 这种关键的瘤抑制屏障的分子触发大多是未知的.
研究的目的:
- 确定复制危机程序的分子调节器.
- 阐明Z-DNA结合蛋白1 (ZBP1) 在端粒介导的瘤抑制中的作用.
主要方法:
- 研究Z-DNA结合蛋白1 (ZBP1) 作为复制危机的调节剂.
- 通过cGAS-STING途径检查了与危机相关的ZBP1异型的诱导.
- 评估ZBP1通过包含端粒重复的RNA (TERRA) 的激活及其定位到线粒体.
- 研究ZBP1寡合化和线粒体抗病毒信号蛋白 (MAVS) 的激活.
主要成果:
- 确定ZBP1是复制危机的关键调节者.
- 一个ZBP1异型是由cGAS-STING诱导的,但需要来自功能障碍的端粒的TERRA才能完全激活.
- 与TERRA结合的ZBP1在线粒体上形成纤维,激活MAVS并启动干扰素反应.
- 作为干扰素反应的信号放大机制,ZBP1的寡合化作用.
结论:
- 功能障碍的端粒通过线粒体TERRA- ZBP1复合体激活先天免疫反应.
- 这种机制消除了具有瘤潜力的细胞,揭示了端粒介导的瘤抑制途径.
- 在感知端粒功能障碍和启动免疫反应方面,ZBP1的作用对于瘤抑制至关重要.
更多相关视频
09:15Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells
Published on: October 20, 2022
2.3K
06:25Quantifying Replication Stress in Ovarian Cancer Cells Using Single-Stranded DNA Immunofluorescence
Published on: February 10, 2023
2.1K
相关概念视频
02:15Replicative Cell Senescence
3.7K
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...
3.7K
02:41Telomeres and Telomerase
23.6K
In eukaryotic DNA replication, a single-stranded DNA fragment remains at the end of a chromosome after the removal of the final primer. This section of DNA cannot be replicated in the same manner as the rest of the strand because there is no 3’ end to which the newly synthesized DNA can attach. This non-replicated fragment results in gradual loss of the chromosomal DNA during each cell duplication. Additionally, it can induce a DNA damage response by enzymes that recognize single-stranded...
23.6K
02:37Restarting 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
01:29Replication in Eukaryotes
14.1K
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...
14.1K
01:02The DNA Replication Fork
36.3K
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...
36.3K
02:37DNA 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