From tRNA to miRNA: RNA‐folding contributes to correct entry into noncoding RNA pathways

Abstract

Edited by Wilhelm JustAlthough RNA are synthesized as single-stranded molecules, most of them are characterized by extensive secondary structures. Two RNA that require distinct folding for biogenesis and function are miRNA and tRNA. While miRNA are processed from hairpin-containing precursors, tRNA are folded into characteristic L-shaped structures. In addition, tRNA and their precursors are a rich source of RNA fragments. Recent findings suggest that their production might be determined by structural characteristics of the tRNA substrates. Importantly, correct folding of pre-tRNA is assisted by the Lupus autoantigen La, an RNA chaperone. In this context, La interacts with pre-tRNA to prevent alternative foldings leading to mis-channeling into the miRNA pathway. Thus, RNA chaperones also function as gatekeepers for correct RNA pathway selection.Keywords: Lupus autoantigen La; miRNA; RNA chaperone; tRNA fragments RNA molecules are characterized by secondary structures that are important for their individual functions. Such structures can be restricted to short sequence stretches or can involve distant regions of large RNA molecules as known for the complex folding of rRNA, for example [1]. Shorter RNA, such as tRNA, small nuclear RNA (snRNA), or small nucleolar RNA (snoRNA), often adopt specific structures providing RNA-or protein-binding platforms or scaffolds for ribonucleoprotein particle (RNP) formation. Other RNA including miRNA or short interfering RNA (siRNA) use distinct folding strategies of precursor molecules, which allow efficient processing to their mature and functional forms [2]. Therefore, adopting the correct structure is vital for any RNA molecule and processes have evolved that support RNA folding and the stability of RNA structures [3]. Biogenesis of tRNAOne class of RNA that requires a very specific folding to fulfill its functions is tRNA. In addition, tRNA are highly modified at various nucleotides and these alterations can also dramatically affect the secondary structure (reviewed in [4]). In eukaryotes, tRNA are transcribed by RNA polymerase III (pol III) as precursor molecules that contain a 5 0 extension and a 3 0 trailer terminating with a stretch of U residues. The 5 0 extension (often referred to as 5 0 leader) is removed by RNase P. The human RNase P is a RNP complex composed of 10 protein subunits and the noncoding RNA H1 (or RPPH1) [5], which is transcribed by pol III as well. RNA H1 is the catalytic subunit and therefore RNase P was among the first ribozymes that has been discovered [6].The canonical processing of the 3 0 end of pre-tRNA requires the endonucleolytic cleavage activity of a Abbreviations ANG, angiogenin; LARP, La-related protein; RBP, RNA-binding protein; RISC, RNA-induced silencing complex; RNP, ribonucleoprotein particle; siRNA, short interfering RNA; snoRNA, small nucleolar RNA; snRNA, small nuclear RNA; tRF, tRNA fragment; TSEN, tRNA-splicing endonuclease.

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Single-molecule mechanical unfolding kinetics of unmodified Saccharomyces cerevisiae tRNAPhe: a hint to the tRNA chaperone-tRNA interaction mechanism

“…The folding state and folding kinetics affect many processes in the life cycle of a tRNA molecule. In the tRNA maturation and degradation processes in eukaryotic cells, proteins or complexes such as Lupus autoantigen, RNase P, exportin-t, tRNA nucleotidyltransferase and xrn-1 interact with pre-tRNA or tRNA substrates by virtue of their structural characteristics (1)(2)(3)(4)(5). Moreover, tRNAs may change their folding state during some essential biological processes.…”