Noncanonical functions of microRNAs in the nucleus

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs (ncRNAs) that play their roles in the regulation of physiological and pathological processes. Originally, it was assumed that miRNAs only modulate gene expression post-transcriptionally in the cytoplasm by inducing target mRNA degradation. However, with further research, evidence shows that mature miRNAs also exist in the cell nucleus, where they can impact gene transcription and ncRNA maturation in several ways. This review provides an overview of novel models of nuclear miRNA functions. Some of the models remain to be verified by experimental evidence, and more details of the miRNA regulation network remain to be discovered in the future.

1. Introduction

MicroRNAs are a category of endogenous, noncoding small RNAs that have approximately 19–24 nucleotides in length and regulate gene expression through various mechanisms. Since their discovery in 1993 [1], extensive research has been conducted. miRNAs play a critical role in many metabolic processes, including cell differentiation, lineage specification, reprogramming, immune response, and the cell cycle [2‒6]. Moreover, miRNAs are well known to be closely linked to various kinds of diseases, including cancer [7‒9]. Given their association with numerous pathological processes, miRNAs possess significant potential as biological drug targets, and tissue-specific miRNAs can also serve as biomarkers [10,11]. For medical research in this field, it is worth noting that numerous miRNAs are evolutionarily conserved [12], permitting researchers to investigate them using Drosophila, Mus musculus, and even plant models.

Originally, miRNAs were believed to regulate gene expression in a negative manner posttranscriptionally in the cytoplasm. In this conventional pathway, the transcription of a primary miRNA (pri-miRNA) occurs from a miRNA gene, aided by RNA polymerase II (Pol II) or Pol III [13,14]. Next, Drosha and DiGeorge syndrome critical region 8 (DGCR8) cleave the pri-miRNA into pre-miRNA, which is then exported to the cytoplasm with the help of Exportin-5 [15‒18]. In the cytoplasm, Dicer cleaves the pre-miRNA into a miRNA duplex [13,14], which is unwound by cytoplasmic Argonaute (Ago) protein. One strand is loaded into the miRISC, while the other strand is degraded [19]. Subsequently, miRISC serves as a negative regulator to mediate translational repression or mRNA degradation [13,14].

The recruitment of miRNAs to their targets depends mainly on the sequence complementarity between them. The canonical miRNA-target interactions are mediated by the seed sequence, which is a region of 6–8 nucleotides on the 5′ end of the miRNA that forms Watson-Crick base pairs with the target [20]. Noncanonical miRNA-target interactions also exist in the functions of numerous miRNAs, such as miR-24 and let-7 [21,22]. Some of these interactions do not follow simple seed sequence pairing and contain multiple mismatches, bulges and wobbles, indicating that miRNA targeting modes may be complex and flexible.

Over time, evidence has emerged supporting the existence of mature miRNAs in the nucleus [23‒28]. Numerous mechanisms of nuclear miRNA functions have been discovered, including their interactions with DNA, RNA, and proteins [29‒32], which suggests that nuclear miRNAs play a critical role in the overall miRNA-related gene regulation network (Figure 1). This review primarily concentrates on nuclear functional miRNAs, summarizing research conducted in this field in recent years.