MicroRNA-independent roles of the RNase III enzymes Drosha and Dicer

Abstract

The ribonuclease III enzymes Drosha and Dicer are renowned for their central roles in the biogenesis of microRNAs (miRNAs). For many years, this has overshadowed the true versatility and importance of these enzymes in the processing of other RNA substrates. For example, Drosha also recognizes and cleaves messenger RNAs (mRNAs), and potentially ribosomal RNA. The cleavage of mRNAs occurs via recognition of secondary stem-loop structures similar to miRNA precursors, and is an important mechanism of repressing gene expression, particularly in progenitor/stem cell populations. On the other hand, Dicer also has critical roles in genome regulation and surveillance. These include the production of endogenous small interfering RNAs from many sources, and the degradation of potentially harmful short interspersed element and viral RNAs. These findings have sparked a renewed interest in these enzymes, and their diverse functions in biology.

Keywords: Dicer; Drosha; RNA processing; RNase III enzymes; microRNA.

Figure 1.

Structural characteristics of RNase III family members. The family is subdivided into three classes based on domain organization. Class I enzymes are found only in bacteria and simple eukaryotes, and are believed to be the antecedents of the more complex class II and III enzymes. All RNase III family members contain a dsRNA binding domain and RNase III domain, responsible for cleaving dsRNA. Evolution of these enzymes in higher eukaryotes led to the accumulation of additional domains. Of note is the acquisition of a helicase domain in many Dicer enzymes, which is likely to be important for unwinding dsRNA duplexes, and the PAZ domain, which binds to the 3′ end of target dsRNA. While in Drosha, proline-rich (P-rich) and/or arginine serine rich (RS-rich) domains are present in most species. The function(s) of these two domains is unclear, but they may function in protein–protein interactions.

Figure 2.

dsRNA substrates of Drosha and Dicer. dsRNA structures that can be recognized and processed by the RNase III enzymes Drosha and Dicer. Drosha cleaves various stem-loop structures similar to pri-miRNAs, such as within mRNAs, DNA-damage-induced RNAs and possibly pre-ribosomal RNA (pre-rRNA). Dicer can cleave a large number of different substrates with internal double-stranded structures, in addition to pre-miRNAs. These include endogenous dsRNAs to produce siRNAs, triplet repeat RNAs, SINE-derived RNAs and DNA-damage-induced RNAs.