RNA-binding proteins and exoribonucleases modulating miRNA in cancer: the enemy within

Abstract

Recent progress in the investigation of microRNA (miRNA) biogenesis and the miRNA processing machinery has revealed previously unknown roles of posttranscriptional regulation in gene expression. The molecular mechanistic interplay between miRNAs and their regulatory factors, RNA-binding proteins (RBPs) and exoribonucleases, has been revealed to play a critical role in tumorigenesis. Moreover, recent studies have shown that the proliferation of hepatocellular carcinoma (HCC)-causing hepatitis C virus (HCV) is also characterized by close crosstalk of a multitude of host RBPs and exoribonucleases with miR-122 and its RNA genome, suggesting the importance of the mechanistic interplay among these factors during the proliferation of HCV. This review primarily aims to comprehensively describe the well-established roles and discuss the recently discovered understanding of miRNA regulators, RBPs and exoribonucleases, in relation to various cancers and the proliferation of a representative cancer-causing RNA virus, HCV. These have also opened the door to the emerging potential for treating cancers as well as HCV infection by targeting miRNAs or their respective cellular modulators.

Fig. 1. Schematic diagram of the structure of miRNA-modulating RBPs with functional domains and motifs.

The hnRNP family (left). hnRNPs have different molecular weights ranging from 34 to 120-kDa, and approximately 20 major hnRNPs, from Al to U, have been characterized in humans. Among the hnRNP family, several representatives known to be involved in miRNA regulation were selected for presentation. Three unique RNA-binding domains (RBDs) in hnRNP family members are required for RNA binding. RRM, RNA recognition motif; KH, K-homology domain; and RGG, RNA-binding domain consisting of Arg-Gly-Gly repeats. Various miRNA-modulating RBPs with functional domains and motifs (right). Lin28A contains a cold-shock domain (CSD) and CCHC-type Zn finger motifs for nucleic acid binding. Lin28B also contains a CSD, CCHC-type Zn finger motifs for nucleic acid binding, and a C-terminal Ser/Lys-rich motif. ELAVL1/HuR contains three RRMs (RRM1–3) for RNA recognition. KSRP contains four KH domains (KH1–4) for RNA recognition. TRIM71/LIN41 contains a RING (Really Interesting New Gene) domain for E3 ubiquitin ligase activity, two B-boxes, a coiled-coil domain, a filamin domain, and a unique C-terminal NHL (NCL-1, HT2A2, and LIN41)-repeat motif for RNA binding. ARS2 contains an N-terminal nuclear localization signal (NLS), a domain of unknown function (DUF), a central RRM motif for RNA substrate binding, a zinc finger (ZnF), and a C-terminal proline-rich unique nuclear cap-binding complex (CBC)-binding motif. TARBP contains two double-stranded RNA binding domains (dsRBDs), and C4 in the Medipal region is required for its interaction with Dicer. ADAR1 and ADAR2 contain dsRBDs and an adenosine (A)-to-inosine (I)-deamination catalytic domain. DEAD-box RNA helicases contain a common DEAD (Asp-Glu-Ala-Asp) motif for ATP-binding and a helicase domain. A detailed description of the RBPs, with their functional domains and motifs is provided in the text.

Fig. 2. RBP action and interplay in pri-miRNA regulation.

The figure illustrates several examples of the mechanism of action of RBP-mediated pri-miRNA regulation in cancer. RBPs have posttranscriptional mechanistic interactions with various pri-miRNA transcripts and the Drosha-DGCR8 microprocessor complex. Consequently, RBP-triggered miRNA-dependent signaling pathways affect tumor progression. A detailed description of the mode of action is provided in the text.

Fig. 3. RBP action in pre-miRNA regulation.

The figure illustrates several examples of the mechanism of action of RBP-mediated pre-miRNA regulation in cancer. RBPs have posttranscriptional mechanistic interactions with various pre-miRNAs and the Dicer-TARBP microprocessor complex. Consequently, RBP-triggered miRNA-dependent signaling pathways affect tumor progression. A detailed description of the mode of action is provided in the text.

Fig. 4. RBP action in mature miRNA regulation, miRISC formation, and miRNA targeting to the mRNAs.

The figure illustrates several examples of the mechanisms of action of RBP-mediated mature miRNA regulation in cancer. RBPs have posttranscriptional mechanistic interactions with mature miRNAs, the key catalytic engine for miRISC formation (AGO2), and target mRNAs. Consequently, RBP-triggered miRNA-dependent signaling pathways affect tumor progression. A detailed description of the mode of action is provided in the text.

Fig. 5. Schematic diagram of the structure of miRNA-modulating exoribonucleases with functional domains and motifs.

The 5′–3′ exoribonuclease XRN1 contains two conserved regions, CR1 and CR2, within the nuclease domain, a PAZ domain, a winged helix domain, and an SH3-like motif. The 5′–3′ exoribonuclease XRN2 also contains CR1 and CR2 within its nuclease domain. The 3′–5′ exoribonuclease PARN contains an R3H (arginine-three amino acid residues-histidine) motif within the nuclease domain, an RRM, and a CTD (C-terminal domain). The 3′–5′ exoribonuclease ERI1 contains a SAP domain for nucleic acid binding and a nuclease domain. In the DIS3 3′–5′ exoribonuclease family, DIS3 and DIS3L contain a PilT N-terminal (PIN) domain, but DIS3L2 does not; all DIS3 family members contain two tandem cold-shock domains (CSD1 and CSD2) for nucleic acid binding, a ribonuclease II (RNB) catalytic domain that supports RNA degradation, and an S1 domain in the C-terminal region that is known to confer substrate RNA binding. A detailed description of various exoribonucleases, with their functional domains and motifs, is provided in the text.

Fig. 6. Exoribonuclease action in pre-miRNA regulation.

The figure illustrates several examples of the mechanism of action of exoribonuclease-mediated pre-miRNA regulation in cancer. Various exoribonucleases have posttranscriptional mechanistic interactions with various pre-miRNAs. Consequently, exoribonuclease-triggered miRNA-dependent signaling pathways affect tumor progression. A detailed description of the mode of action is provided in the text.

Fig. 7. Exoribonuclease action in mature miRNA regulation.

The figure illustrates several examples of the mechanism of action for exoribonuclease-mediated mature miRNA regulation in cancer. Various exoribonucleases have posttranscriptional mechanistic interactions with various naïve or posttranscriptionally modified mature miRNA species. Consequently, exoribonuclease-triggered miRNA maturation/trimming/degradation-dependent signaling pathways affect tumor progression. A detailed description of the mode of action is provided in the text.

Fig. 8. Effects of various RBPs and exoribonucleases on HCV genomic RNA and the HCV guardian miR-122.

During HCV proliferation, hnRNP K may function as a key modulator of HCV RNA replication by recruiting intracellular miR-122 to HCV RNA. ELAVL1/HuR can physically bind to the 3′-end of miR-122 and positively influence the expression of miR-122. ELAVL1/HuR also significantly affects HCV proliferation through miR-122 regulation. XRN1 and XRN2 can compete with miR-122 for HCV RNA synthesis, whereas hnRNP E2 may compete with miR-122 for HCV RNA to facilitate HCV translation. A detailed description of the mode of action is provided in the text.