Sweet dicer: impairment of micro-RNA processing by diabetes.

Abstract

Micro-RNAs (miRNAs) are small noncoding RNAs that control gene expression epigenetically. miRNA genes are transcribed by RNA polymerase II into a primary transcript—the primary miRNA that consists of at least 1 hairpin structure, with the characteristic long stem and a terminal loop. Mature miRNAs will be typically generated from the primary transcripts after 2 cleavage events (Figure): the first cleavage occurs in the nucleus by an RNAse III, the Drosha–DGCR8 complex, from primary miRNAs to pre-miRNAs. The second cleavage takes place in the cytosol where pre-miRNAs are further cleaved by Dicer, and the mature miRNAs are loaded into the RNA-induced silencing complex.1 Although platelets lack a nucleus, there are several lines of evidence suggesting a functional miRNA pathway in platelets: (1) platelets contain miRNAs and express both Dicer (required for cleavage of pre-miRNAs to mature miRNAs) and Argonaute 2 (required for RNA-mediated gene silencing by the RNA-induced silencing complex)2 and (2) they are also major contributors to the circulating miRNA pool as evidenced by significant positive correlations to platelet microparticles3 and a marked reduction on antiplatelet therapy.4 Figure. miRNA biogenesis and impairment in diabetic platelets (marked with pins). On transcription by RNA polymerase II, the primary miRNA (pri-miRNAs) is processed to a precursor miRNA (pre-miRNA) by the Drosha–DGCR8 (DiGeorge syndrome chromosomal [or critical] region 8) complex. The pre-miRNA is then exported from the nucleus into the cytosol by Exportin-5. Before the mature miRNAs are loaded into the RNA-induced silencing complex (RISC), the pre-miRNA hairpin has to be cleaved by Dicer. The latter step is impaired in diabetic platelets because of increased calpain activity. Calpain targets Dicer for proteolytic degradation. Because platelets lack a …