Noncoding RNA Surveillance: The Ends Justify the Means

Abstract

Numerous surveillance pathways sculpt eukaryotic transcriptomes by degrading unneeded, defective, and potentially harmful noncoding RNAs (ncRNAs). Because aberrant and excess ncRNAs are largely degraded by exoribonucleases, a key characteristic of these RNAs is an accessible, protein-free 5' or 3' end. Most exoribonucleases function with cofactors that recognize ncRNAs with accessible 5' or 3' ends and/or increase the availability of these ends. Noncoding RNA surveillance pathways were first described in budding yeast, and there are now high-resolution structures of many components of the yeast pathways and significant mechanistic understanding as to how they function. Studies in human cells are revealing the ways in which these pathways both resemble and differ from their yeast counterparts, and are also uncovering numerous pathways that lack equivalents in budding yeast. In this review, we describe both the well-studied pathways uncovered in yeast and the new concepts that are emerging from studies in mammalian cells. We also discuss the ways in which surveillance pathways compete with chaperone proteins that transiently protect nascent ncRNA ends from exoribonucleases, with partner proteins that sequester these ends within RNPs, and with end modification pathways that protect the ends of some ncRNAs from nucleases.

A new pathway of pre-tRNA surveillance in yeast

“…RTD may also be in competition with the trafficking machinery, since mature cytoplasmic tRNA lacking m 2,2 G is degraded by RTD or is subject to retrograde import into the nucleus (50). This model of opportunistic decay is similar to the previously proposed scavenger mechanism attributed to RNA quality control pathways that also monitor tRNAs in Escherichia coli (89)(90)(91).…”

The RNA exosome nuclease complex regulates human embryonic stem cell differentiation

“…In hESCs, NMD enhances mesoderm formation and limits definitive endoderm, although the mRNA targets responsible were not identified ( Lou et al, 2016 ). Notably, human cells contain many pathways by which defective and potentially harmful mRNAs and ncRNAs can be targeted for decay ( Schoenberg and Maquat, 2012 ; Belair et al, 2018 ). These pathways are often functionally overlapping, as it is often necessary to deplete multiple pathways to see significant accumulation of a specific target ( Belair et al, 2018 ).…”

“…Notably, human cells contain many pathways by which defective and potentially harmful mRNAs and ncRNAs can be targeted for decay ( Schoenberg and Maquat, 2012 ; Belair et al, 2018 ). These pathways are often functionally overlapping, as it is often necessary to deplete multiple pathways to see significant accumulation of a specific target ( Belair et al, 2018 ). Given that hESCs must both maintain the pluripotent state and retain the ability to rapidly differentiate in response to environmental signals, RNA surveillance pathways may function widely to degrade RNAs whose presence compromises hESC function.…”

Distinct and evolutionary conserved structural features of the human nuclear exosome complex

“…Degradation of the 5' ETS, a byproduct of ribosome biogenesis, is also a function of both yeast and human nucleolar exosome complexes, but different cofactors are involved ( Sudo et al, 2016 ). The major function of the human nuclear exosome, however, appears to lie in quality control pathways that counteract pervasive transcription initiation and defective transcription termination ( Belair et al, 2018 ; Ogami et al, 2018 ; Szczepińska et al, 2015 ). For example, the nucleoplasmic exosome targets prom oter u p stream t ranscripts (PROMPTs) that arise due to antisense transcription from bidirectional promoters ( Preker et al, 2008 ) and prematurely terminated products of protein coding genes ( Szczepińska et al, 2015 ).…”