SNPs in 3'UTR miRNA Target Sequences Associated with Individual Drug Susceptibility

Abstract

The complementary interaction of microRNAs (miRNAs) with their binding sites in the 3'untranslated regions (3'UTRs) of target gene mRNAs represses translation, playing a leading role in gene expression control. MiRNA recognition elements (MREs) in the 3'UTRs of genes often contain single nucleotide polymorphisms (SNPs), which can change the binding affinity for target miRNAs leading to dysregulated gene expression. Accumulated data suggest that these SNPs can be associated with various human pathologies (cancer, diabetes, neuropsychiatric disorders, and cardiovascular diseases) by disturbing the interaction of miRNAs with their MREs located in mRNA 3'UTRs. Numerous data show the role of SNPs in 3'UTR MREs in individual drug susceptibility and drug resistance mechanisms. In this review, we brief the data on such SNPs focusing on the most rigorously proven cases. Some SNPs belong to conventional genes from the drug-metabolizing system (in particular, the genes coding for cytochromes P450 (CYP 450), phase II enzymes (SULT1A1 and UGT1A), and ABCB3 transporter and their expression regulators (PXR and GATA4)). Other examples of SNPs are related to the genes involved in DNA repair, RNA editing, and specific drug metabolisms. We discuss the gene-by-gene studies and genome-wide approaches utilized or potentially utilizable to detect the MRE SNPs associated with individual response to drugs.

Keywords: 3′untranslated regions (3′UTRs); PASSPORT-seq; VEGFR1; allele-specific expression (ASE); drug response; luciferase reporter assay; miRNA target sites; microRNA (miRNA); pharmacogenes; single nucleotide polymorphisms (SNPs).

Figure 1

(A) Principal scheme of discovery of functional SNPs that result in changes of microRNA binding to their response elements in the mRNA 3’UTR; (B) the hypothetical mechanism of the individual drug response due to the mirSNP. SNP(A>G) in 3′UTR of mRNA leads to the gain of the miRNA response element allowing miRNA-mRNA binding which hinders gene expression at a posttranscriptional level.

Figure 2

Putative mechanism underlying the effect of rs7326277 on the level of induced expression of VEGFR1 gene. (A) Before the treatment with dexamethasone or vitamin D, the expression of this gene in a human primary cell line (HUVEC) is at a background level (dashed arrow); (B) dexamethasone activates the glucocorticoid receptor (GR) and the receptor interacts with the GRE in distant region of VEGFR1 gene (ENCODE), activating transcription (solid arrow). The mRNA molecules carrying rs7326277 allele G bind miR-193a-5p in the MRE site in 3′UTR, decreasing the number of mRNA copies as a result of degradation. (C) The interaction of vitamin D (its active derivative) with its receptor (VDR) activates VEGFR1 gene transcription (solid arrow) via the binding of VDR/RXR heterodimeric complex with the three VDRE sites in intron 1 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE145584) (accessed on 10 October 2022). Allelic imbalance is determined by the miR-193a-5p–mediated decrease in the number of the mRNA copies carrying rs7326277 allele G.

Figure 3

Putative mechanism underlying the effect of rs3209896 from the 3′UTR of AKR1C3 gene. (A) Before the treatment with selenium-containing preparations, the expression of this gene in a human primary cell line (HUVEC) is at a background level (dashed arrow); (B) selenium preparations can activate either FAK/PI3K/AKT or redox signaling pathway, resulting in binding of transcription factors with their sites in the AKR1C3 regulatory region, and triggers transcription (solid arrow). The mRNA molecules carrying rs3209896 allele A bind miR-4290 or miR-4687-5p in the MRE site of 3′UTR, thereby decreasing the mRNA copy number as a result of degradation.