DEAD-Box RNA Helicases in Cell Cycle Control and Clinical Therapy

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.

Keywords: DDX3; DDX5; DEAD-box RNA helicases; cell cycle; treatment.

Figure 1

Schematic representation of the cell cycle. The cell cycle is divided into interphase (G1, S, G2) and mitotic phases. Nondividing cells are in G0. Cell cycle progression is controlled by cyclin/cyclin-dependent kinase (CDK) complexes in specific cell cycle phases.

Figure 2

The sequence motifs of DEAD-box RNA helicases family are conserved. The DEAD-box RNA helicases family is characterized by a minimum of 12 conserved domains to form the DEAD-box helicase core, which consists of two RecA-related domains. Domain I and II contains 7 and 5 sequence motifs, respectively. The motifs of Q, I, II, and VI function as ATP binding and hydrolysis, and the motifs of Ia, Ib, Ic, IV, IVa, and V function as RNA binding. The motifs III and Va function as coordination between RNA and ATP binding. Domain II includes the DEAD motif (asp-Glu-ala-asp). The DEAD-box RNA helicases usually contain N and C terminal extensions, which determine their interaction with specific RNA and/or protein.

Figure 3

Schematic representation of the RNA helicases which are involved in the regulation of the cell cycle. RNA helicases are involved in G1/S transition: DDX3 positively regulates cyclin E1 translation but negatively regulates KLF4 expression to increase CDK2 expression. DHX33 initiates the transcription of E2F1, cyclin E2, cyclin D1, MMP9, MCMs, CDC6, and CDC20. DHX9 decreases the transcription of CDK6, leading to CIZ1 nuclear translocation. DDX21 activates c-Jun transcription, resulted in the increase of the synthesis of cyclin D1 mRNA. eIF4A regulates G1/S transition through regulation of the translation of cyclin D1, cyclin D2, and CDK6. RNA helicases are involved in S phase progression: DDX51 promotes S phase progression, possibly through negative regulation of cell-cycle-related proteins, p53-p21. RNA helicases are involved in G2-M phase transition: DDX56 promotes G2/M transition via the increase of intron retention and tumor suppressor WEE1 expression. RNA helicases are involved in mitotic phase progression: Knockdown of UAP56 or URH49 leads to mitosis defect. DDX6/CGH-1 functions to regulate microtubule cytoskeleton and chromosome separation. RNA helicases regulate the expression of CDK inhibitor p21: DDX41 and p68 inhibit p21 transcription and translation, respectively.