通过Cr-DNA损伤激活ATR是一个主要的生存反应,在Cr (VI) 暴露后建立S和G2检查点
Sophia Valiente1, Casey Krawic1, Anatoly Zhitkovich1
1Brown University, Legorreta Cancer Center, Department of Pathology and Laboratory Medicine, Providence, RI 02912, USA.
Toxicology and applied pharmacology
|September 21, 2023
概括
六价 (Cr(VI)) 暴露会导致肺癌. 亚酸盐恢复的细胞激活ATR激酶,感知DNA损伤并形成细胞周期检查点,揭示了Cr (VI) 抵抗机制.
科学领域:
- 毒理学 毒理学 毒理学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 吸入六价 (Cr(VI)) 是已知的肺癌和肺毒性的原因.
- 的细胞代谢产生反应性中间体和DNA损伤.
- 阿斯科伯酸盐 (Asc) 在体内影响Cr (VI) 的代谢,影响DNA损伤的形成.
研究的目的:
- 为了研究DNA损伤反应应激通路在暴露于Cr(VI) 的人类肺细胞中在阿斯酸盐恢复条件下的作用.
- 了解不同生物损伤形式在Cr (VI) 毒性的重要性.
主要方法:
- 人类肺细胞暴露于Cr (VI) 时,阿斯酸盐 (Asc) 恢复.
- 研究了对蛋白质和DNA损伤敏感应激反应的激活,包括ATR和ATM激酶.
- 在ATR抑制后评估了细胞周期进展和细胞活力.
主要成果:
- 阿斯克恢复的细胞显示抑制了氧化剂敏感应激,但强烈激活ATR激酶.
- ATR信号发送始于S阶段末期,并持续到G2阶段.
- ATR抑制损害了细胞周期检查点,并降低了受Cr (VI) 治疗的肺细胞的活力,包括类似干细胞.
结论:
- 一个关键的Cr(VI) 抵抗机制涉及ATR在S阶段晚期对Cr-DNA损伤的感知.
- 激活ATR导致保护细胞周期检查点,减轻Cr (VI) 毒性.
- 在Cr (VI) 暴露后,ATR在肺细胞存活中发挥着关键作用,即使在低剂量中也是如此.
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