升高的活性氧物种可以驱动ATRX-null癌症中端粒途径的替代延长
Tomas Goncalves1, Siobhan Cunniffe2, Tiffany S Ma2
1MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
Nucleic acids research
|February 8, 2025
概括
活性氧物种 (ROS) 驱动ATRX缺陷质瘤中端粒 (ALT) 途径的替代延长,通过引起DNA:RNA混合体和DNA-蛋白质交叉链接. 减少ROS或解决R循环可能会提供新的癌症疗法.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症遗传学 癌症遗传学
背景情况:
- 端粒的替代延长 (ALT) 途径是一种与端粒酶独立的机制,可使癌细胞不朽化,经常在质瘤和骨髓瘤中观察到.
- 虽然ATRX损失在ALT阳性癌症中很常见,但其他细胞事件,如DNA:RNA混合 (R-loop) 积累和DNA-蛋白交联 (DPC) 形成,都与此有关,但不太了解.
- 在ALT癌症中形成R环和DPC的精确内源触发因素仍然难以捉摸.
研究的目的:
- 研究活性氧物种 (ROS) 在ATRX缺陷质瘤中ALT通路激活中的作用.
- 为了确定ALT阳性质瘤中ROS升高的来源.
- 阐明ROS,R环,DPC和ALT通路活动之间的机制联系.
主要方法:
- 对ALT阳性质瘤中ROS水平的分析.
- 研究导致ROS升高的遗传和环境因素 (SETD2共变,DRG2下调,低氧).
- 对ROS水平和RNase H1活性进行实验操纵,以评估对R循环形成和ALT通路活性的影响.
- 评估DNA-蛋白质交叉链接的形成,特别是TOP1cc,与R循环相关.
主要成果:
- 过度的细胞ROS被确定为ATRX缺陷质瘤中ALT通路激活的关键驱动因素.
- 确定了三种ROS升高的主要来源:SETD2共变,DRG2下调和缺氧瘤微环境.
- 通过RNase H1活性减少R循环,抑制了ROS升高的细胞中的ALT通路.
- 在R循环形成和DPC积累之间确立了因果关系,包括TOP1cc.
- 升高的ROS触发了骨髓瘤和质瘤细胞系中ALT通路的过度活性,导致DNA损伤和细胞死亡.
结论:
- 升高的ROS是一个关键的内源因素,在ALT阳性癌症中启动R循环和DPC形成.
- 通过RNase H1介导的R循环分解为ALT驱动的癌症提供了潜在的治疗策略.
- 了解ROS-ALT轴为挑战质瘤和骨肉瘤等恶性瘤提供了新的治疗途径.
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