针对ZDHHC12介导的PARP1棕化增强了PARP抑制剂的细胞毒性
Xining Zhang1, Ye Liu2, Xingming Liao3
1Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, China.
Cell reports
|January 25, 2026
概括
可逆S-palmitoylation通过影响PARP1染色体结合来调节PARPi聚合酶抑制剂. 抑制ZDHHC12介导的PARP1棕化可以克服卵巢癌中PARPi的抗性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- 聚ADP-核糖) 聚合酶抑制剂 (PARPi) 通过在DNA损伤部位捕获PARP1对癌症治疗至关重要.
- 对PARPi的临床耐药性仍然是治疗高度血清性卵巢癌 (HGSOC) 等癌症的重要障碍.
研究的目的:
- 研究蛋白质翻译后修改在调节PARP1功能和PARPi反应中的作用.
- 为了确定克服PARPi抗性的新目标.
主要方法:
- 质谱测量以识别和定位PARP1棕化.
- 在体外测试评估PARP1的DNA结合和捕获.
- HGSOC的细胞和异种移植模型用于评估药物敏感性.
- 对棕甲基转移酶和脱棕甲基酶的基因操纵.
主要成果:
- 在PARP1的DNA结合域中,它经历了可逆的S-palmitoylation,在其DNA结合域中的保存的囊蛋白中进行.
- DNA损伤降低了PARP1的棕化,增强了它的染色体参与.
- 棕甲基转移酶ZDHHC12催化了PARP1的棕化;它的抑制增强了PARP1的捕获,并使HGSOC细胞对Niraparib敏感.
- 来自患者的PARP1变种通过独立于直接突变位点棕化的一种机制表现出耐药性.
结论:
- 可逆S-palmitoylation作为PARP1染色体参与的负调节剂.
- 通过ZDHHC12介导的PARP1棕化是克服HGSOC中PARPi抗性的可针对性的漏洞.
- 向ZDHHC12提供了一种潜在的策略,以使抗性瘤对PARPi疗法重新敏感.
相关概念视频
01:27Cytotoxic T Cells-mediated Immune Response
6.6K
Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
6.6K
01:52Eukaryotic Transcription Inhibitors
10.9K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
10.9K
00:52Potential Energy
42.4K
The energy stored by a structure and location of matter in space is called potential energy. For instance, raising a kettlebell changes its spatial location and increases its potential energy. Similarly, a stretched rubber band contains potential energy which, under certain conditions, can be converted into other forms of energy, such as kinetic energy.
Chemical bonds that form attractive forces between atoms also contain potential energy, called chemical energy. When a chemical reaction...
Chemical bonds that form attractive forces between atoms also contain potential energy, called chemical energy. When a chemical reaction...
42.4K
01:09Potential Energy
985
A conservative force, such as a gravitational or elastic force, gives the body the capacity to do work. This capacity, measured as the potential energy, depends on the body's location or “position” relative to a fixed reference position or datum. The gravitational potential energy is considered zero at the reference point. Suppose a body is located at some vertical distance above a fixed horizontal reference or datum. In that case, the weight of the body has positive gravitational potential...
985
03:02Standard Electrode Potentials
50.0K
On comparing the reactivity of silver and lead, it is observed that the two ionic species, Ag+ (aq) and Pb2+ (aq), show a difference in their redox reactivity towards copper: the silver ion undergoes spontaneous reduction, while the lead ion does not. This relative redox activity can be easily quantified in electrochemical cells by a property called cell potential. This property is commonly known as cell voltage in electrochemistry, and it is a measure of the energy which accompanies the charge...
50.0K
01:39Receptor-mediated Endocytosis
110.7K
Overview
110.7K