Mutagen-specific mutation signature determines global microRNA binding.

Eyal Greenberg,Oz Solomon,Gideon Rechavi,Jacob Schachter,Gal Markel,Ninette Amariglio,Eran Eyal

doi:10.1371/journal.pone.0027400

Eyal Greenberg, Oz Solomon + Show 5 more

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https://doi.org/10.1371/journal.pone.0027400

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Abstract

Micro-RNAs (miRNAs) are small non-coding RNAs that regulate gene products at the post-transcriptional level. It is thought that loss of cell regulation by miRNAs supports cancer development. Based on whole genome sequencing of a melanoma tumor, we predict, using three different computational algorithms, that the melanoma somatic mutations globally reduce binding of miRNAs to the mutated 3′UTRs. This phenomenon reflects the nature of the characteristic UV-induced mutation, C-to-T. Furthermore, we show that seed regions are enriched with Guanine, thus rendering miRNAs prone to reduced binding to UV-mutated 3′UTRs. Accordingly, mutation patterns in non UV-induced malignancies e.g. lung cancer and leukemia do not yield similar predictions. It is suggested that UV-induced disruption of miRNA-mediated gene regulation plays a carcinogenic role. Remarkably, dark-skinned populations have significantly higher GC content in 3′UTR SNPs than light-skinned populations, which implies on evolutionary pressure to preserve regulation by trans-acting oligonucleotides under conditions with excess UV radiation.

Highlights

Melanoma is one of the main life-threatening malignancies of our era, accounting for 75% of skin cancer–related deaths worldwide [1]
Mutations in the 39 un-translated region (39UTR) found in melanoma globally reduce miRNA binding
single nucleotide variants (SNV) analysis between melanoma cells and normal melanocytes revealed a,1:1 ratio between those found within coding sequences and untranslated regions (UTRs) of known genes [31]

Summary

Introduction

Melanoma is one of the main life-threatening malignancies of our era, accounting for 75% of skin cancer–related deaths worldwide [1]. MiRNAs are small, non-coding, 19–22 nucleotide long RNA strands, which function as specific epigenetic regulators of gene expression by inhibiting protein translation, leading mRNA to degradation, or both [6,7]. Nearly 1000 human miRNAs have been identified [8], and those are thought to regulate more than 50% of human genes [9]. Not surprisingly, their expression pattern is frequently perturbed in developmental diseases and cancer, which can directly exert phenotypic effects [10,11,12, 13,14,15]. Exemplar miRNAs include the inhibitory miRNAs miR-34a [19], miR-193b [20], let-7a [21], and miR-211 [22,23], while miR-182 [24] and miR-221/222 [22] were shown to stimulate metastatic potential of melanoma cells

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