可卡因诱导的DNA-PK通过促进TRIM28酸化来缓解RNAP II暂停
Adhikarimayum Lakhikumar Sharma1, Priya Tyagi1, Meenata Khumallambam1
1Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
bioRxiv : the preprint server for biology
|September 4, 2024
概括
可卡因激活了DNA依赖蛋白激酶 (DNA-PK),促进了HIV的转录和复制. 这种激活通过修改参与HIV生命周期的关键蛋白质来增强病毒基因表达.
科学领域:
- 分子生物学分子生物学
- 病毒学 病毒学
- 药理学 药理学是指药理学的学科.
背景情况:
- 滥用药物,特别是使用可卡因,是有效控制艾滋病毒的重要障碍.
- 了解可卡因影响HIV复制的分子机制对于开发有针对性的干预措施至关重要.
研究的目的:
- 阐明可卡因增强HIV转录和复制的分子途径.
- 为了确定参与可卡因诱导的HIV基因表达的关键蛋白质相互作用和修饰.
主要方法:
- 研究了可卡因对DNA依赖蛋白激酶 (DNA-PK) 表达和激活的影响.
- 使用细胞测试分析了DNA-PK招募到HIV的长终端重复 (LTR).
- 检查了RNA聚合酶II (RNAP II) CTD和TRIM28.28的酸化状态.
- 评估了循环林依赖激酶 (CDK) 和转录延长因子的活性.
主要成果:
- 可卡因可调节并激活DNA-PK,促进其核转移和向HIV LTR招募.
- 可卡因诱导的DNA-PK通过促进RNAP IICTD酸化在Ser5和Ser2.2,从而增强HIV转录.
- 可卡因激活CDK7,导致CDK9酸化和增强P-TEFb活动.
- 可卡因在酸824中特别化TRIM28,将其从抑制剂转化为HIV转录的激活剂.
结论:
- 可卡因通过激活DNA-PK和随后对关键转录调节者的修改,显著增强了HIV转录和复制.
- 这些发现揭示了治疗策略的新分子标,旨在减轻可卡因对艾滋病毒感染者的不良影响.
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