RNA helicase DHX33 was found to regulate the transcription of multiple genes involved in cancer development. But the underlying molecular mechanism remains unclear. Here, we found DHX33 associated extensively with gene promoters at CG-rich region. Its deficiency reduced the loading of active RNA polymerase II at gene promoters. Furthermore, we observed a functional interaction between DHX33, AP-2β, and DNA demethylation protein Gadd45a (growth arrest and DNA damage inductile protein 45a) at specific gene promoters. DHX33 is required to recruit GADD45a, thereby causing local DNA demethylation through further recruiting ten-eleven-translocation (Tet) methylcytosine dioxygenase enzyme, as manifested by reduced 5-hydroxymethyl cytosine levels for a subset of genes after DHX33 deficiency. This process might involve R-loop formation in GC skew as a guidance signal at promoter sites. Our report provides for the first time, to our knowledge, original evidence that DHX33 alters epigenetic marks and regulates specific gene transcription through interaction with Gadd45a.

中文翻译：

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DHX33招募Gadd45a导致DNA去甲基化并调节基因转录的子集。

发现RNA解旋酶DHX33调节参与癌症发展的多个基因的转录。但是潜在的分子机制仍不清楚。在这里，我们发现DHX33与富含CG的区域的基因启动子广泛相关。它的缺乏降低了基因启动子上活性RNA聚合酶II的负荷。此外，我们观察到DHX33，AP-2β和DNA去甲基化蛋白Gadd45a之间的功能相互作用（生长停滞和DNA损伤诱导蛋白45a）在特定基因启动子处。DHX33需要募集GADD45a，从而通过进一步募集10-11易位（Tet）甲基胞嘧啶双加氧酶来引起局部DNA去甲基化，这表现为DHX33缺乏后一部分基因的5-羟甲基胞嘧啶水平降低。该过程可能涉及GC偏斜中的R环形成，作为启动子位点的指导信号。据我们所知，我们的报告首次提供了DHX33通过与Gadd45a相互作用来改变表观遗传标记并调节特定基因转录的原始证据。