Impact of RNA Modifications and RNA-Modifying Enzymes on Eukaryotic Ribonucleases

Constitutive and regulated turnover of RNAs is necessary to eliminate aberrant RNA molecules and control the level of specific mRNAs to maintain homeostasis or to respond to signals in living cells. Modifications of nucleosides in specific RNAs are important in modulating the functions of these transcripts, but they can also dramatically impact their fate and turnover. This chapter will review how RNA modifications impact the activities of ribonucleases that target these RNAs for degradation or cleavage, focusing more particularly on tRNAs and mRNAs in eukaryotic cells. Many nucleoside modifications are important to promote proper folding of tRNAs, and the absence of specific modifications makes them susceptible to degradation by quality control pathways that eliminate improperly folded species. Modifications in tRNAs can also modulate their cleavage during stress or by fungal toxins that target modified nucleosides. Modifications of the cap structure found at the 5'-end of eukaryotic mRNAs are essential to control the degradation of these mRNAs. In addition, internal modifications of eukaryotic mRNAs can change their secondary structures or provide binding sites for reader proteins, which can dramatically impact their stability. Recent examples show that mRNA modifications play important roles in regulating mRNA stability during development, cellular differentiation and physiological responses. Finally, many modifications can impact microRNA- and siRNA-mediated gene regulation by direct or indirect effects. With the growing number of genomic techniques able to identify modifications genome wide, it is anticipated that novel chemical modifications or new modification sites will be identified, which will play additional regulatory functions for RNA turnover.