DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle.
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.
Department of Biology, Southern University of Science and Technology, Shenzhen, China.
Baolei
B
Yuan
Department of Biology, Southern University of Science and Technology, Shenzhen, China.
Xingshun
X
Wang
Department of Biology, Southern University of Science and Technology, Shenzhen, China.
Chunyan
C
Fan
Department of Biology, Southern University of Science and Technology, Shenzhen, China.
Jin
J
You
Department of Biology, Southern University of Science and Technology, Shenzhen, China.
Yuchu
Y
Liu
ICCE Institute, Department of Internal Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA.
Jason D
JD
Weber
Department of Biology, Southern University of Science and Technology, Shenzhen, China zhonghb@sustc.edu.cn zhangyd@sustc.edu.cn.
Hanbing
H
Zhong
Department of Biology, Southern University of Science and Technology, Shenzhen, China zhonghb@sustc.edu.cn zhangyd@sustc.edu.cn.
Yandong
Y
Zhang
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D015854:Up-Regulation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D029961:Zebrafish Proteins; D012319:RNA Polymerase II; C568925:DHX33 protein, human; D053487:DEAD-box RNA Helicases; C000620272:DHX33 protein, zebrafish