DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle
DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle
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DHX33 转录控制参与细胞周期的基因
DOI：
10.1128/mcb.00314-16
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发表时间：
2016-12-01
影响因子：
5.3
通讯作者：
Zhang, Yandong
中科院分区：
文献类型：
--
作者：
Yuan, Baolei;Wang, Xingshun;Zhang, Yandong
摘要RNA解旋酶DHX33是细胞增殖和生长的重要调节因子。然而，DHX33功能背后的潜在机制仍不完全清楚。我们在多个细胞系中提供了原始证据，证明DHX33在转录上控制参与细胞周期的基因的表达，特别是细胞周期蛋白、E2F1、细胞分裂周期（CDC）和微型染色体维持（MCM）基因。DHX33与这些基因的启动子物理结合，并控制活性RNA聚合酶II加载到这些启动子上。DHX33缺陷会破坏细胞周期进程和DNA复制，并导致细胞凋亡。在斑马鱼中，CRISPR介导的DHX33敲除导致DHX33敲除胚胎中细胞周期蛋白A2、细胞周期蛋白B2、细胞周期蛋白D1、细胞周期蛋白E2、cdc6、cdc20、E2F1和MCM复合物的下调。此外，我们发现DHX33在非小细胞肺癌和Ras突变的人肺癌细胞系中过表达。这些癌细胞中DHX33的强制减少在体内消除了肿瘤形成。我们的研究首次证明DHX33作为一种直接的转录调节因子，促进细胞周期的进展，并在胚胎发育和肿瘤发生过程中驱动细胞增殖中发挥重要作用。
ABSTRACT The RNA helicase DHX33 has been shown to be a critical regulator of cell proliferation and growth. However, the underlying mechanisms behind DHX33 function remain incompletely understood. We present original evidence in multiple cell lines that DHX33 transcriptionally controls the expression of genes involved in the cell cycle, notably cyclin, E2F1, cell division cycle (CDC), and minichromosome maintenance (MCM) genes. DHX33 physically associates with the promoters of these genes and controls the loading of active RNA polymerase II onto these promoters. DHX33 deficiency abrogates cell cycle progression and DNA replication and leads to cell apoptosis. In zebrafish, CRISPR-mediated knockout of DHX33 results in downregulation of cyclin A2, cyclin B2, cyclin D1, cyclin E2, cdc6, cdc20, E2F1, and MCM complexes in DHX33 knockout embryos. Additionally, we found the overexpression of DHX33 in a subset of non-small-cell lung cancers and in Ras-mutated human lung cancer cell lines. Forced reduction of DHX33 in these cancer cells abolished tumor formation in vivo. Our study demonstrates for the first time that DHX33 acts as a direct transcriptional regulator to promote cell cycle progression and plays an important role in driving cell proliferation during both embryo development and tumorigenesis.