Nuclear RNA decay

Nuclear RNA decay In addition to protein coding mRNAs and stable RNAs such as rRNAs, tRNAs, snoRNAs, and snRNAs, the human genome is pervasively transcribed (Clark et al. 2011) to yield other non-coding RNAs such as enhancer transcripts, promoter upstream transcripts (PROMPTs, Preker et al. 2008), long non-coding RNAs (lncRNAs), and apparently non-functional transcripts (reviewed in Ogami and Suzuki 2021). In addition, processing intermediates and abortive transcripts are produced during transcription of mRNAs and stable RNAs. In the nucleus, pervasive unstable transcripts are degraded by nucleases such as the RNA exosome complex (a 3'-5' exonuclease), XRN2 (a 5'-3' exonuclease), and DXO (a 5'-3' exonuclease and a decapping enzyme) (reviewed in Wolin and Maquat 2019, Rambout and Maquat 2024). RNA substrates are directed to the RNA exosome by the nuclear exosome targeting (NEXT) complex, the poly(A) tail exosome targeting (PAXT) connection, and the Trf4/5-Air1/2-Mtr4 polyadenylation (TRAMP) complex. This sorting is crucial to the removal of malformed transcripts and misassembled RNA-protein complexes (reviewed in Wolin and Maquat 2019, Garland and Jensen 2024). Through ZC3H18 or ZC3H4, the NEXT complex (RBM7:ZCCHC8:MTREX) binds capped nonpolyadenylated RNAs (Wu et al. 2020), such as abortive transcripts from RNA polymerase II, recruits the RNA exosome, then the MTREX (MTR4, SKIV2L2) subunit of NEXT unwinds the RNA for introduction into the barrel-shaped RNA exosome (Lubas et al. 2011, Andersen et al. 2013). The PAXT connection (ZFC3H1:MTREX) targets more mature, capped and polyadenylated transcripts (Meola et al. 2016, Wu et al. 2020), and the nucleolar TRAMP complex (MTREX:TENT4A,B:ZCCHC7) targets processing products of rRNA maturation (Sudo et al. 2016). The 5'-3' exonuclease XRN2 is active on RNAs that possess a 5' monophosphate group (inferred from the yeast homolog in Stevens and Poole 1995), but is blocked by a 5' triphosphate or cap structure (reviewed in Miki and Großhans 2013, Nagarajan et al. 2013). Substrates of XRN2 include decapped RNAs and the 3' cleavage products of RNA polymerase II transcripts (reviewed in Miki and Großhans 2013, Nagarajan et al. 2013). The decapping 5'-3 exonuclease DXO can both remove 5' triphosphate or caps (especially unmethylated caps) and exonucleolytically hydrolyze RNAs (Jiao et al. 2013, Doamekpor et al. 2020). DXO is also active on nicotinamide adenine dinucleotide (NAD) cap on RNAs (Jiao et al. 2017) and other "metabolic caps" (several activities and references can be added here, see below). The exonuclease activity of DXO is distributive, while that for XRN2 is processive. The human TRAMP complex is found in a complex with the RNA exosome in the nucleolus where it directs the 5' external transcribed sequence that is cleaved from the 47S pre-rRNA during production of the 45S pre-rRNA (Lubas et al. 2011, Sudo et al. 2016).