Abstract
Cell cycle is regulated through numerous signaling pathways that determine whether cells will proliferate, remain quiescent, arrest, or undergo apoptosis. Abnormal cell cycle regulation has been linked to many diseases. Thus, there is an urgent need to understand the diverse molecular mechanisms of how the cell cycle is controlled. RNA helicases constitute a large family of proteins with functions in all aspects of RNA metabolism, including unwinding or annealing of RNA molecules to regulate pre-mRNA, rRNA and miRNA processing, clamping protein complexes on RNA, or remodeling ribonucleoprotein complexes, to regulate gene expression. RNA helicases also regulate the activity of specific proteins through direct interaction. Abnormal expression of RNA helicases has been associated with different diseases, including cancer, neurological disorders, aging, and autosomal dominant polycystic kidney disease (ADPKD) via regulation of a diverse range of cellular processes such as cell proliferation, cell cycle arrest, and apoptosis. Recent studies showed that RNA helicases participate in the regulation of the cell cycle progression at each cell cycle phase, including G1-S transition, S phase, G2-M transition, mitosis, and cytokinesis. In this review, we discuss the essential roles and mechanisms of RNA helicases in the regulation of the cell cycle at different phases. For that, RNA helicases provide a rich source of targets for the development of therapeutic or prophylactic drugs. We also discuss the different targeting strategies against RNA helicases, the different types of compounds explored, the proposed inhibitory mechanisms of the compounds on specific RNA helicases, and the therapeutic potential of these compounds in the treatment of various disorders.
Highlights
RNA helicases are highly conserved enzymes important for RNA metabolism, which are involved in multiple steps of cell cycle regulation (Figure 3)
RNA helicases are involved in cell cycle regulation at each phase with different mechanisms of action, including the regulation of (1) pre-mRNA transcription or splicing of some cell cycle regulators, (2) translation of cell cycle stage associated cyclins and Cy pendent kinases (CDKs), and (3) transcriptional and post-translational modification of the effectors, such as p21, that are involved in cell cycle progression
DDX3 regulates the expression of cyclin A1, cyclin E1, and CDK2
Summary
The cell cycle is a series of events that occur in the interphase and mitotic phase (M-phase) [1,2]. The activated E2F regulates the transcription of genes involved in cell cycle progression, including CDK2, cyclins A and E, and DNA synthesis, to promote G1/S transition [38,39]. Upregulation of DDX21 promotes breast cancer cell proliferation by activation of the transcription factor AP-1 to regulate the transcription of cyclin D1 and rRNA processing, resulting in the increase of cells in the S phase (Figure 3) [65,69]. The binding of eIF4A3 to LncRNA H19 prevents the recruitment of eIF4A3 to the mRNAs of the cell cycle regulators, including cyclin D1 and cyclin E1, for post-transcriptional modification, resulting in an acceleration of colon cancer cell growth [73,76]. Whether DDX46 regulates G1/S phase transition through Akt and IκBα needs to be further investigated
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