Reactome | Nuclear RNA decay

Nuclear RNA decay

Stable Identifier

R-HSA-9930044

DOI

10.3180/R-HSA-9930044.2

Type

Pathway

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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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).

Literature References

PubMed ID	Title	Journal	Year
27434818	Interaction properties of human TRAMP-like proteins and their role in pre-rRNA 5'ETS turnover Sudo, H, Nozaki, A, Uno, H, Ishida, Y, Nagahama, M	FEBS Lett	2016
23523372	A mammalian pre-mRNA 5' end capping quality control mechanism and an unexpected link of capping to pre-mRNA processing Jiao, X, Chang, JH, Kilic, T, Tong, L, Kiledjian, M	Mol Cell	2013
24270879	The human cap-binding complex is functionally connected to the nuclear RNA exosome Andersen, PR, Domanski, M, Kristiansen, MS, Storvall, H, Ntini, E, Verheggen, C, Schein, A, Bunkenborg, J, Poser, I, Hallais, M, Sandberg, R, Hyman, A, LaCava, J, Rout, MP, Andersen, JS, Bertrand, E, Jensen, TH	Nat Struct Mol Biol	2013
7608167	5'-exonuclease-2 of Saccharomyces cerevisiae. Purification and features of ribonuclease activity with comparison to 5'-exonuclease-1 Stevens, A, Poole, TL	J Biol Chem	1995
21765801	The reality of pervasive transcription Clark, MB, Amaral, PP, Schlesinger, FJ, Dinger, ME, Taft, RJ, Rinn, JL, Ponting, CP, Stadler, PF, Morris, KV, Morillon, A, Rozowsky, JS, Gerstein, MB, Wahlestedt, C, Hayashizaki, Y, Carninci, P, Gingeras, TR, Mattick, JS	PLoS Biol	2011
19056938	RNA exosome depletion reveals transcription upstream of active human promoters Preker, P, Nielsen, J, Kammler, S, Lykke-Andersen, S, Christensen, MS, Mapendano, CK, Schierup, MH, Jensen, TH	Science	2008
34948199	Nuclear RNA Exosome and Pervasive Transcription: Dual Sculptors of Genome Function Ogami, K, Suzuki, HI	Int J Mol Sci	2021
38637632	Nuclear mRNA decay: regulatory networks that control gene expression Rambout, X, Maquat, LE	Nat Rev Genet	2024
23517755	XRN 5'→3' exoribonucleases: structure, mechanisms and functions Nagarajan, VK, Jones, CI, Newbury, SF, Green, PJ	Biochim Biophys Acta	2013
21855801	Interaction profiling identifies the human nuclear exosome targeting complex Lubas, M, Christensen, MS, Kristiansen, MS, Domanski, M, Falkenby, LG, Lykke-Andersen, S, Andersen, JS, Dziembowski, A, Jensen, TH	Mol. Cell	2011
23863139	The multifunctional RNase XRN2 Miki, TS, Großhans, H	Biochem Soc Trans	2013
28283058	5' End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA Decay through DXO-Mediated deNADding Jiao, X, Doamekpor, SK, Bird, JG, Nickels, BE, Tong, L, Hart, RP, Kiledjian, M	Cell	2017
31777937	A novel 5'-hydroxyl dinucleotide hydrolase activity for the DXO/Rai1 family of enzymes Doamekpor, SK, Gozdek, A, Kwasnik, A, Kufel, J, Tong, L	Nucleic Acids Res	2020
32075771	A Two-Layered Targeting Mechanism Underlies Nuclear RNA Sorting by the Human Exosome Wu, G, Schmid, M, Rib, L, Polak, P, Meola, N, Sandelin, A, Jensen, TH	Cell Rep	2020
39366352	Nuclear sorting of short RNA polymerase II transcripts Garland, W, Jensen, TH	Mol Cell	2024