Cytoplasmic RNA Decay

Abstract

Abstract RNA (ribonucleic acid) molecules play vital roles in the eukaryotic cells, not only as mediators of the flow of genetic information from DNA (deoxyribonucleic acid) to proteins but also as potent regulators of gene expression in general. Ubiquitous transcription of the eukaryotic genome, occurring in the cell nucleus, leads to the synthesis of multiple precursor RNA molecules, which undergo class‐dependent, very often complex processing events, eventually generating mature transcripts, such as mRNAs, tRNAs and rRNAs, serving as templates, adaptors and effectors, respectively, during translation. In addition, numerous noncoding RNAs (ncRNAs) are produced, which fine‐tune gene expression at different stages. Protein‐coding transcripts and many ncRNAs exert their functions in the cytoplasm. Levels of different RNA species are controlled by numerous cytoplasmic decay pathways, largely dependent on specific modifications of transcripts' ends and various enzymatic activities, including endo‐ and exoribonucleases. Moreover, RNA molecules are scrutinised for errors which may potentially impair their function by dedicated surveillance mechanisms. Key Concepts Eukaryotic genomes are almost entirely transcribed, giving rise to mRNAs, which code for proteins, and to multiple noncoding RNA classes, which impact gene expression at different levels. Posttranscriptional regulation of RNA stability represents one of the major means of controlling expression of genetic information in eukaryotes. Cytoplasm is the site of RNA decay for those transcripts which function in this subcellular compartment. Cytoplasmic mRNA decay in eukaryotes can be initiated by internal endonucleolytic cleavage or, more frequently, through digestion of nucleotides starting at the 5′‐ or the 3′‐end and carried out by 5′ to 3′ or 3′ to 5′ exoribonucleases, respectively. mRNA termini are protected by the 5′‐cap structure and (with the exception of mammalian histone‐coding transcripts) 3′ poly(A) tail with bound proteins; these protective elements are usually removed before exonucleolytic degradation. Poly(A) tail shortening (deadenylation) and extension with untemplated uridine residues (uridylation) are the most common signals triggering exonucleolytic mRNA degradation; nonpolyadenylated mRNA coding for replication‐dependent histones in mammals can also undergo uridylation, which may stimulate removal of the protective 3′ stem‐loop structure. Deadenylation or uridylation provokes cap elimination from the 5′‐end (decapping) and 5′–3′ decay by Xrn1 enzyme; alternatively, mRNA can be degraded in the opposite (3′–5′) direction by the catalytic activities associated with the multisubunit exosome complex or in an exosome‐independent pathway controlled by DIS3L2 exonuclease, stimulated by uridylation. Aberrant mRNAs, containing premature termination codons, devoid of stop codons or messengers, on which ribosomes tend to stall during translation, are removed by cytoplasmic quality control mechanisms, such as NMD, NSD and NGD. A common feature of these surveillance pathways is their dependence on ongoing protein synthesis. Notably, final phases of faulty mRNA decay in NMD/NSD/NGD are essentially carried out by the same exonucleases which control regular mRNA turnover. One of the major NMD factors is Upf1 RNA helicase, which interacts with a dimer of canonical ribosome release factors, eRF3 GTPase‐eRF1, when translation terminates on premature stop codon. On the contrary, NSD and NGD are Upf1‐independent processes, employing Ski7 GTPase‐like protein and Hbs1–Dom34 complex, structurally resembling eRF3–eRF1 dimer. Quality of some stable ncRNAs, such as tRNAs and rRNAs, can also be interrogated in the cytoplasm by dedicated surveillance mechanisms, which depend to some extent on regular and aberrant mRNA decay factors. Decay pathways for a diversified group of unstable RNA species, generated by ubiquitous transcription or untypical processing of larger molecules, are less well characterised, and for some ncRNA classes remain obscure. Depending on the organism and transcript architecture, different enzymes can be involved in removal of such transcripts from the cytoplasm of wild‐type cells. Some ncRNAs are degraded by nucleases that control mRNA fate, such as Xrn1, exosome and DIS3L2, but for other noncoding transcripts, unique cytoplasmic degradative pathways emerged during evolution.