林导向酵母和人类MAP激酶酸化了Dot1p/DOT1L基因素H3K79甲基转移酶
Ryan J Separovich1, Nicola M Karakatsanis1, Kelley Gao1
1Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.
The FEBS journal
|January 25, 2024
概括
该研究确定Hog1p是Dot1p酸化的关键激酶,Dot1p是H3K79甲基化的关键酶. 这种酸化对酵母DNA损伤反应至关重要,并保留在人类DOT1L.
科学领域:
- 表观遗传学和翻译后修改
- 细胞信号通道 细胞信号通道
- 对DNA损伤的反应机制
背景情况:
- 端粒沉默1 (Dot1p) 的破坏者是酵母中唯一的H3K79甲基转移酶,对端粒沉默至关重要.
- Dot1p在体内被大量化,但其上游激酶在真核生物中基本上未被识别.
- 了解Dot1p调节对于破译表观遗传控制和DNA修复途径至关重要.
研究的目的:
- 为了确定负责Saccharomyces cerevisiae中的Dot1p酸化的上游激酶.
- 阐明Dot1p酸化在细胞反应中的功能意义,特别是对DNA损伤的作用.
- 为了研究已识别的激酶-Dot1p调节轴的进化保存.
主要方法:
- 采用了体外和体内激酶发现方法来识别Dot1p相互作用的激酶.
- 使用了体外激酶试验来确认酸化位点和Hog1p基质特异性.
- 在酵母中进行基因组删除和酸突变分析,并进行表型评估.
- 在哺乳动物系统中研究了基因酶活性,使用正义蛋白质.
主要成果:
- 线素激活蛋白激酶HOG1 (Hog1p) 被确定为Dot1p的直接激酶.
- Hog1p在多个位点化Dot1p,包括与林相邻的残留物,在Pbs2p激活时活性增强.
- Hog1p介导的Dot1p酸化对于细胞抵抗紫外线诱导的DNA损伤至关重要.
- 人类的正统对象DOT1L被p38β (MAPK11) 酸化,表明受保护的调节.
结论:
- 霍格1p是一种新型和必需的上游激酶,调节酵母中的H3K79甲基转移酶Dot1p.
- 在DNA损伤反应途径中,Dot1p的Hog1p依赖酸化起着至关重要的作用.
- 在Hog1p/p38β和Dot1p/DOT1L之间酶基质关系在真核生物中保持.
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