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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >In vivo stabilization of the Dnmt1 (cytosine-5)-methyltransferase protein
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In vivo stabilization of the Dnmt1 (cytosine-5)-methyltransferase protein

机译：Dnmt1（cytosine-5）-甲基转移酶蛋白的体内稳定化

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摘要

The Dnmt1o form of the Dnmt1 (cytosine-5)-methyltransferase enzyme is synthesized and stored in the cytoplasm of the oocyte and is used after fertilization to maintain methylation patterns on imprinted genes. After implantation of the blastocyst, Dnmt1o is replaced by the Dnmt1 form, which has an additional 118 aa at its amino terminus. To investigate functional differences between Dnmt1o and Dnmtl, mice were generated with a mutant allele, Dnmt1~v, which synthesized Dnmt1o instead of Dnmt1 in all somatic cells. Homozygous Dnmt1~v mice were phenotypically normal, and had normal levels of genomic methylation, indicating that Dnmt1o adopts the maintenance methyltransferase function of Dnmt1. Despite the apparent equivalence of Dnmt1o and Dnmt1 maintenance methyltransferase function in somatic cells, the Dnmt1o protein was found at high levels (with a corresponding high enzymatic activity) in Dnmt1~v mice. In heterozygous Dnmt1~v/+ embryonic stem cells and early embryos, equal steady-state levels of Dnmt1o and Dnmt1 proteins were produced from the Dnmt1~v and the WT Dnmt1 alleles, respectively. However, in older embryos and adults, the Dnmt1~v allele produced five times the steady-state level of protein of the WT Dnmt1 allele. The difference in Dnmt1o and Dnmt1 levels is due to a developmentally regulated mechanism that degrades the Dnmt1 protein. The intrinsic stability of the Dnmt1o protein is the most likely reason for its use as a maternal-effect protein; stable ooplasmic stores of Dnmt1o would be available to traffick into the nuclei of the eight-cell stage embryo and maintain methylation patterns on alleles of imprinted genes during the fourth embryonic S phase.
机译：Dnmt1（cytosine-5）-methyltransferase Dnmt1o形式被合成并存储在卵母细胞的细胞质中，受精后用于维持印迹基因的甲基化模式。植入胚泡后，Dnmt1o替换为Dnmt1形式，该形式在其氨基末端具有118个氨基酸。为了研究Dnmt10和Dnmt1之间的功能差异，用突变的等位基因Dnmt1〜v产生了小鼠，该突变体在所有体细胞中合成了Dnmt1o而不是Dnmt1。纯合子Dnmt1〜v小鼠在表型上正常，基因组甲基化水平正常，表明Dnmt1o具有Dnmt1的维持甲基转移酶功能。尽管在体细胞中Dnmt1o和Dnmt1维持甲基转移酶功能具有明显的等效性，但在Dnmt1〜v小鼠中发现Dnmt1o蛋白处于高水平（具有相应的高酶促活性）。在杂合的Dnmt1〜v / +胚胎干细胞和早期胚胎中，Dnmt1〜v和WT Dnmt1等位基因分别产生相等的稳态水平的Dnmt1o和Dnmt1蛋白。然而，在较老的胚胎和成年小鼠中，Dnmt1〜v等位基因产生的稳态蛋白质水平是野生型Dnmt1等位基因的五倍。 Dnmt10和Dnmt1水平的差异是由于降解Dnmt1蛋白的发育调控机制所致。 Dnmt1o蛋白的内在稳定性是其被用作母体效应蛋白的最可能原因。 Dnmt1o的稳定的卵质储存将可用于贩运到八细胞期胚胎的细胞核中，并在第四个胚胎S期维持印记基因等位基因的甲基化模式。

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