美國猶他州大學(xué)腫瘤科學(xué)系,，藥物化學(xué)系，霍華休斯醫(yī)學(xué)院,，Huntsman癌癥研究所以及Roswell Park癌癥研究所藥理與治療學(xué)系的研究者在DNA去甲基化的研究上取得新的進(jìn)展,，相關(guān)成果公布在最新一期（12月26日）的Cell上。
脊椎動(dòng)物的DNA去甲基化問題一直以來都備受關(guān)注,，盡管到目前為止相關(guān)的研究理論已經(jīng)積累了不少,，但是去甲基化的準(zhǔn)確機(jī)制或是參與其中的酶這兩個(gè)方面的研究一直沒有取得突破性的進(jìn)展。以斑馬魚胚胎為研究對(duì)象,，Bradley研究人員取得了新的進(jìn)展,，研究結(jié)果表明，細(xì)胞內(nèi)去除5-methylcytosine（5-meC）必須要有5-meC deaminase（簡(jiǎn)稱AIDS,，5-meC脫氨基酶,，可將5-meC轉(zhuǎn)化為胸腺嘧啶）與G:T mismatch-specific thymine glycosylase（Mbd4）同時(shí)發(fā)揮作用。如果在胚胎中注射一些甲基化的DNA會(huì)誘導(dǎo)細(xì)胞產(chǎn)生去甲基化活性,，如果細(xì)胞缺失AID或是缺失酶因子Gadd45則去甲基化的活性將被削弱,。
值得關(guān)注的是，活細(xì)胞中過度表達(dá)AID或是Mbd4會(huì)引起基因組大面積的發(fā)生去甲基化,。此外,，敲除AID或是Mbd4會(huì)導(dǎo)致普通基因產(chǎn)生再次的甲基化作用。最終，Gadd45具有促進(jìn)去甲基化以及增強(qiáng)AID與Mbd4間的相互作用的功能,。
研究成果最終表明,，5-meC去甲基化是由一個(gè)雙因子控制機(jī)制控制的，首先AID去氨基化,，接下來胸腺嘧啶的堿基被Mbd4切除,，這一過程由Gadd45因子其促進(jìn)作用,。（生物谷Bioon.com）
生物谷推薦原始出處：
Cell,26 December 2008 doi:10.1016/j.cell.2008.11.042
DNA Demethylation in Zebrafish Involves the Coupling of a Deaminase, a Glycosylase, and Gadd45
Kunal Rai1,3,4,Ian J. Huggins4,Smitha R. James5,Adam R. Karpf5,David A. Jones1,2,4,,andBradley R. Cairns1,3,4,,
1 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
2 Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA
3 Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84112, USA
4 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
5 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
Evidence for active DNA demethylation in vertebrates is accumulating, but the mechanisms and enzymes remain unclear. Using zebrafish embryos we provide evidence for 5-methylcytosine (5-meC) removal invivo via the coupling of a 5-meC deaminase (AID,which converts 5-meC to thymine) and a G:T mismatch-specific thymine glycosylase (Mbd4). The injection of methylated DNA into embryos induced a potent DNA demethylation activity, which was attenuated by depletion of AID or the non enzymatic factor Gadd45. Remarkably, overexpression of thedeaminase/glycosylase pair AID/Mbd4 invivo caused demethylation of the bulk genome and injected methylated DNA fragments, likely involving a G:T intermediate. Furthermore, AID or Mbd4 knockdown caused the remethylation of a set of common genes. Finally, Gadd45 promoted demethylation and enhanced functional interactions between deaminase/glycosylase pairs. Our results provide evidence for a coupled mechanism of 5-meC demethylation, whereby AID deaminates 5-meC, followed by thymine base excision by Mbd4, promoted by Gadd45.
