核酸枯竭通过诱导DNA复制压力诱导细胞命运过渡促进核酸枯竭
Brian T Do1, Peggy P Hsu2, Sidney Y Vermeulen3
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Health Sciences and Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Developmental cell
|June 1, 2024
概括
代谢变化,特别是核酸枯竭和DNA复制压力,触发了血液系统中的细胞分化. 这个过程独立于DNA损伤信号发生,并且可以克服致癌阻碍成熟的障碍.
科学领域:
- 细胞生物学 细胞生物学
- 发展生物学 发展生物学
- 癌症生物学 癌症生物学
背景情况:
- 细胞身份是由发育计划和环境线索,包括营养素的可用性,调节.
- 代谢干扰可以影响细胞状态和分化途径.
- 造血干细胞的分化是一个复杂的过程,对血液形成至关重要,在急性髓性白血病 (AML) 等疾病中经常受到失调.
研究的目的:
- 研究核酸枯竭和DNA复制应激在推动细胞分化中的作用.
- 为了确定复制压力是否可以克服致癌性阻碍血液形成成熟的障碍.
- 探索代谢变化影响细胞状态转换的一般机制.
主要方法:
- 利用人类和小鼠的正常和转变的造血系统,包括患者衍生的AML异种移植.
- 诱导核酸枯竭和复制压力.
- 分析了细胞状态转变,基因表达和调控位激活.
- 操纵转录因子表达以改变基线细胞状态.
主要成果:
- 核酸枯竭和DNA复制压力被发现在各种血液构造环境中驱动分化.
- 这些细胞状态转换始于S阶段,独立于ATR/ATM检查点信号,双链DNA断裂和细胞周期长度.
- 复制压力激活了原始化的调节位点,并诱导了血统适当的成熟基因,即使在瘤转录因子阻止分化时也是如此.
- 改变转录因子表达导致复制压力,诱导特定于替代血统的基因.
结论:
- 复制应激是血液构造系统中细胞分化的一个强有力的诱导因素.
- 这种机制可以覆盖致癌性阻断,并促进对血统适当的成熟.
- 通过复制应激的代谢变化,提供了调节细胞状态转换和血统承诺的一般机制.
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