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通过ATR对MLL的酸化是执行哺乳动物S相检查点所需的
Han Liu1, Shugaku Takeda, Rakesh Kumar
1Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Nature
|September 7, 2010
概括
该MLL基因对S相检查点至关重要,防止DNA在复制过程中受损. 它在MLL白血病中的破坏导致检查点失效和基因组不稳定.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 癌症生物学 癌症生物学
背景情况:
- 细胞周期检查点对于通过防止DNA复制错误来维持基因组完整性至关重要.
- 失去检查点控制有助于基因组不稳定性和癌症的发展.
- 多细胞生物中S相检查点的精确机制需要进一步阐明.
研究的目的:
- 研究MLL基因在哺乳动物S相检查点中的作用.
- 为了确定MLL功能障碍是否导致MLL白血病.
- 阐明MLL在DNA损伤反应中的功能背后的分子机制.
主要方法:
- 用ATR对MLL进行酸化分析,以应对基因毒性压力.
- 评估MLL与SCF(Skp2) E3结合酶的相互作用.
- 染色体免疫沉以研究MLL结合和基因素甲基化.
- 对MLL缺少细胞和MLL突变细胞复制的表型分析.
- 在小鼠骨髓状原生细胞中研究MLL融合.
主要成果:
- 在基因毒性应激时,MLL在血清516的ATR中被酸化,抑制其降解并导致积累.
- 稳定MLL甲基化基素H3氨酸4在晚期复制起源,延迟DNA复制.
- 缺乏MLL的细胞表现出抗辐射DNA合成和基因组异常.
- 用野生类型的MLL进行复制可以挽救S相检查点缺陷,而突变动物却不能.
- MLL合并破坏了ATR介导的MLL稳定,危害了S阶段检查点.
结论:
- 在哺乳动物S相检查点网络中,MLL是一种新的效应因子.
- 由于MLL变化的检查点功能障碍是MLL白血病的潜在机制.
- 在DNA损伤反应途径中,MLL起着至关重要的作用,其放松调节有助于癌症的发病.
相关概念视频
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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
02:36DNA Damage Can Stall the Cell Cycle
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M cyclin...
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Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
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