MicroRNAs, macrocontrol: regulation of miRNA processing

Abstract

MicroRNAs (miRNAs) are a set of small, non-protein-coding RNAs that regulate gene expression at the post-transcriptional level. Maturation of miRNAs comprises several regulated steps resulting in approximately 22-nucleotide single-stranded mature miRNAs. Regulation of miRNA expression can occur both at the transcriptional level and at the post-transcriptional level during miRNA processing. Recent studies have elucidated specific aspects of the well-regulated nature of miRNA processing involving various regulatory proteins, editing of miRNA transcripts, and cellular location. In addition, single nucleotide polymorphisms in miRNA genes can also affect the processing efficiency of primary miRNA transcripts. In this review we present an overview of the currently known regulatory pathways of miRNA processing and provide a basis to understand how aberrant miRNA processing may arise and may be involved in pathophysiological conditions such as cancer.

FIGURE 1.

MicroRNA processing regulation by Drosha binding or Drosha-associated proteins. (A) Primary miRNA transcript (Pri-miRNA) is processed by Drosha/DGCR8 complex to precursor miRNA (Pre-miRNA). (B) SMAD associates with pri-miR-21, p68, and Drosha/DGCR8 complex to enhance pri-miR-21 processing. (C) Association of p53 with pri-miR-16-1 and pri-miR-143, p68, and Drosha/DGCR8 enhances pri-miR-16-1 and pri-miR-143 processing. (D) p68/p72 complex mediates inhibition of pri-miR-16, pri-miR-125a, pri-miR-143, pri-miR-145, and pri-miR-195 upon stimulation of estrogen receptor α (ER α) by estradiol (E2). (E) Nuclear factor (NF) 90/45 complex inhibits Drosha/DGCR8 processing by binding to stem/loop fragment of pri-miR-21, pri-miR-15a∼16-1, and pri-let-7a-1.

FIGURE 2.

MicroRNA processing regulation by terminal loop binding proteins. (A) Primary miRNA transcript (Pri-miRNA) is processed by Drosha/DGCR8 complex to precursor miRNA (Pre-miRNA) and by Dicer to mature miRNA. Stem and terminal loop (TL) regions are assigned within pri-miRNA. (B) Lin28 protein binds to the terminal loop of pri- and pre-miRNAs from the let-7 family and impairs processing by reducing Drosha and Dicer cleavage and causing uridylation of pre-miR by terminal uridylyl transferase 4 (TUT4) leading to degradation of pre-miR by an unidentified nuclease. (C) Heterogeneous nuclear ribonucleoprotein (hnRNP)-A1 binds to the terminal loop and stem of pri-miR-18a and facilitates its processing by Drosha. (D) KH-type splicing regulatory protein (KSRP) binds to the terminal loop of a set of pri- and pre-miRNAs including let-7a, miR-20, miR-26b, miR-106a, miR-21, miR-16, and enhances both Drosha/DGCR8 and Dicer processing.

FIGURE 3.

Regulation of miRNA processing by ADAR editing. Adenosine deaminases acting on RNA (ADARs) can convert adenosine to inosine in pri-miRNA; conversion of pre-miRNA is also possible, but has not been proven. ADAR editing can lead to blockade in Drosha cleavage of pri-miR-142 and degradation of edited pri-miR-142 by a ribonuclease Tudor-SN. ADAR editing can also block Dicer processing of pri-miR-151 causing accumulation of edited pre-miR-151.

FIGURE 4.

Influence of SNPs on miRNA processing. SNP variants of miR-125a, miR-146, miR-510, miR-196a, and miR-934 are processed differently due to changes in a stem structure or processing sites. Major alleles are situated on the left side; minor alleles on the right.