Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation
Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation
复制标题
DOI：
10.1038/nature05515
复制
发表时间：
2007-02-08
期刊：
影响因子：
64.8
通讯作者：
Niehrs, Christof
中科院分区：
文献类型：
--
作者：
Barreto, Guillermo;Schaefer, Andrea;Niehrs, Christof
DNA甲基化是一种表观遗传修饰，对于许多生物的基因沉默和基因组稳定是必不可少的。尽管促进DNA甲基化的甲基转移酶被很好地描述，但活性DNA去甲基化背后的分子机制却知之甚少，也存在争议(1，2)。在这里，我们发现Gadd45a(生长停滞和DNA损伤诱导蛋白45α)是一种核蛋白，参与维持基因组稳定、DNA修复和抑制细胞生长3、4，在活跃的DNA去甲基化中起关键作用。Gadd45a的过表达激活了甲基化沉默的报告质粒，并促进了全球DNA去甲基化。Gadd45a基因敲除使基因表达沉默，导致DNA高甲基化。在非洲爪哇卵母细胞(5)Oct4的主动去甲基化过程中，Gadd45a被特异性地招募到去甲基化的位置。主动去甲基化通过DNA修复发生，Gadd45a与DNA修复内切酶XPG相互作用并需要DNA修复内切酶XPG。我们得出结论，Gadd45a通过促进DNA修复，消除甲基化标记，缓解了表观遗传基因沉默。
DNA methylation is an epigenetic modification that is essential for gene silencing and genome stability in many organisms. Although methyltransferases that promote DNA methylation are well characterized, the molecular mechanism underlying active DNA demethylation is poorly understood and controversial(1,2). Here we show that Gadd45a ( growth arrest and DNA-damage-inducible protein 45 alpha), a nuclear protein involved in maintenance of genomic stability, DNA repair and suppression of cell growth 3,4, has a key role in active DNA demethylation. Gadd45a overexpression activates methylation-silenced reporter plasmids and promotes global DNA demethylation. Gadd45a knockdown silences gene expression and leads to DNA hypermethylation. During active demethylation of oct4 in Xenopus laevis oocytes(5), Gadd45a is specifically recruited to the site of demethylation. Active demethylation occurs by DNA repair and Gadd45a interacts with and requires the DNA repair endonuclease XPG. We conclude that Gadd45a relieves epigenetic gene silencing by promoting DNA repair, which erases methylation marks.