与Dnmt3L结合的Dnmt3a的结构表明了新的DNA甲基化模式
Da Jia1, Renata Z Jurkowska, Xing Zhang
1Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
Nature
|August 24, 2007
概括
DNA甲基转移酶3类蛋白 (Dnmt3L) 激活DNA甲基转移酶3a (Dnmt3a),以建立基因组印记. 它们在DNA上的相互作用和寡合化产生了一个周期性甲基化模式,这对于印记基因调节至关重要.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 分子生物学分子生物学
- 基因组学就是基因组学.
背景情况:
- 遗传印记调节基因表达基于哺乳动物和植物的父母起源.
- DNA甲基转移酶3a (Dnmt3a) 和DNA甲基转移酶3类蛋白 (Dnmt3L) 对于印制基因的新DNA甲基化至关重要.
- Dnmt3L通过其PHD域结合非甲基化素H3 lysine 4.
研究的目的:
- 阐明Dnmt3L在激活Dnmt3a方面的双重功能的结构基础.
- 了解印制基因中的DNA甲基化机制.
主要方法:
- 进行X射线晶体学以确定Dnmt3a-Dnmt3L复合物的结构.
- 位点定向突变发生,以确定酶活性的关键残留物.
- 分析DNA-Dnmt3a相互作用的分子建模.
- 在印记基因中分析CpG位点周期性.
主要成果:
- Dnmt3L的C端域与Dnmt3a的催化域结合,激活其甲基转移酶活性.
- Dnmt3a和Dnmt3L形成了一个四重体复合体,有两个活性位点.
- 特定的接口对酶活性至关重要.
- Dnmt3a在DNA上寡合,形成一个丝,以8-10个基对的周期性甲基化DNA.
- 这种周期性反映了CpG位点分布在印记基因差异甲基化区域.
结论:
- Dnmt3L可以作为Dnmt3a.a的支架和激活剂.
- 在DNA上的Dnmt3a寡合化决定了周期性甲基化模式.
- 这种机制解释了印记基因中差异甲基化区域的识别和甲基化,整合了基因素修饰和DNA序列间距.
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