tRNA processing in the nucleus (Homo sapiens)
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Description
Genes encoding transfer RNAs are transcribed in the nucleus by RNA polymerase III. (Distinct processes of transcription and processing also occur in mitochondria.) The initial transcripts, pre-tRNAs, contain extra nucleotides at the 5' end and 3' end. 6.3% (32 of 509) of human tRNAs also contain introns, which are located in the anticodon loop, 3' to the anticodon. The additional nucleotides are removed and a non-templated CCA sequence is added to the resulting 3' terminus by processing reactions in the nucleus and cytosol (reviewed in Nakanishi and Nureki 2005, Phizicky and Hopper 2010).
The order of processing and nucleotide modification events may be different for different tRNAs and its analysis is complicated by a retrograde transport mechanism that can import tRNAs from the cytosol back to the nucleus (retrograde movement, Shaheen and Hopper 2005, reviewed in Phizicky 2005). Generally, the 5' leader of the pre-tRNA is removed first by endonucleolytic cleavage by the RNase P ribonucleoprotein complex, which contains a catalytic RNA (RNA H1 in humans) and at least 10 protein subunits (reviewed in Jarrous 2002, Xiao et al. 2002, Jarrous and Gopalan 2010).
The 3' trailer is then removed by RNase Z activity, a single protein in humans (reviewed in Maraia and Lamichhane 2011). ELAC2 is a RNase Z found in both nucleus and mitochondria. ELAC1 is found in the cytosol and may also act as an RNase Z. Human tRNA genes do not encode the universal acceptor 3' terminus CCA, instead it is added post-transcriptionally by TRNT1, an unusual polymerase that requires no nucleic acid template (reviewed in Xiong and Steitz 2006, Hou 2010, Tomita and Yamashita 2014).
In humans introns are spliced from intron-containing tRNAs in the nucleus by a two step mechanism that is distinct from mRNA splicing (reviewed in Popow et al. 2012, Lopes et al. 2015). The TSEN complex first cleaves 5' and 3' to the intron, generating a 2'3' cyclic phosphate on the 5' exon and a 5' hydroxyl group on the 3' exon. These two ends are ligated by a complex containing at least 6 proteins in a single reaction that both hydrolyzes the 2' phosphate bond and joins the 3' phosphate to the 5' hydroxyl. (In yeast the ligation and the hydrolysis of the 2' phosphate are separate reactions. The splicing reactions in yeast occur in the cytosol at the mitochondrial outer membrane.)
Mature transfer RNAs contain a large number of modified nucleotide residues that are produced by post-transcriptional modification reactions (reviewed in Li and Mason 2014). Depending on the specific tRNA these reactions may occur before or after splicing and before or after export from the nucleus to the cytosol. View original pathway at:Reactome.
The order of processing and nucleotide modification events may be different for different tRNAs and its analysis is complicated by a retrograde transport mechanism that can import tRNAs from the cytosol back to the nucleus (retrograde movement, Shaheen and Hopper 2005, reviewed in Phizicky 2005). Generally, the 5' leader of the pre-tRNA is removed first by endonucleolytic cleavage by the RNase P ribonucleoprotein complex, which contains a catalytic RNA (RNA H1 in humans) and at least 10 protein subunits (reviewed in Jarrous 2002, Xiao et al. 2002, Jarrous and Gopalan 2010).
The 3' trailer is then removed by RNase Z activity, a single protein in humans (reviewed in Maraia and Lamichhane 2011). ELAC2 is a RNase Z found in both nucleus and mitochondria. ELAC1 is found in the cytosol and may also act as an RNase Z. Human tRNA genes do not encode the universal acceptor 3' terminus CCA, instead it is added post-transcriptionally by TRNT1, an unusual polymerase that requires no nucleic acid template (reviewed in Xiong and Steitz 2006, Hou 2010, Tomita and Yamashita 2014).
In humans introns are spliced from intron-containing tRNAs in the nucleus by a two step mechanism that is distinct from mRNA splicing (reviewed in Popow et al. 2012, Lopes et al. 2015). The TSEN complex first cleaves 5' and 3' to the intron, generating a 2'3' cyclic phosphate on the 5' exon and a 5' hydroxyl group on the 3' exon. These two ends are ligated by a complex containing at least 6 proteins in a single reaction that both hydrolyzes the 2' phosphate bond and joins the 3' phosphate to the 5' hydroxyl. (In yeast the ligation and the hydrolysis of the 2' phosphate are separate reactions. The splicing reactions in yeast occur in the cytosol at the mitochondrial outer membrane.)
Mature transfer RNAs contain a large number of modified nucleotide residues that are produced by post-transcriptional modification reactions (reviewed in Li and Mason 2014). Depending on the specific tRNA these reactions may occur before or after splicing and before or after export from the nucleus to the cytosol. View original pathway at:Reactome.
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 3' tRNA exon with 5' hydroxyl | Arrow | R-HSA-5696813 (Reactome)  | ||
| 3' tRNA exon with 5' hydroxyl | R-HSA-5696816 (Reactome) | |||
| 5' cleaved pre-tRNA | Arrow | R-HSA-5696810 (Reactome) | ||
| 5' cleaved pre-tRNA | R-HSA-5696815 (Reactome) | |||
| 5' tRNA exon with
2',3' cyclic phosphate | Arrow | R-HSA-5696813 (Reactome) | ||
| 5' tRNA exon with
2',3' cyclic phosphate | R-HSA-5696816 (Reactome) | |||
| 5',3' cleaved pre-tRNA | Arrow | R-HSA-5696815 (Reactome) | ||
| 5',3' cleaved pre-tRNA | R-HSA-5696807 (Reactome) | |||
| AMP | Arrow | R-HSA-5696816 (Reactome) | ||
| ATP | R-HSA-5696807 (Reactome) | |||
| ATP | R-HSA-5696816 (Reactome) | |||
| CTP | R-HSA-5696807 (Reactome) | |||
| Cleaved pre-tRNA
(intron-containing) with 3' CCA | R-HSA-5696813 (Reactome) | |||
| Cleaved tRNA with 3' CCA | Arrow | R-HSA-5696807 (Reactome) | ||
| ELAC2 | mim-catalysis | R-HSA-5696815 (Reactome) | ||
| Nuclear Pore Complex (NPC) | mim-catalysis | R-HSA-6783483 (Reactome) | ||
| PPi | Arrow | R-HSA-5696807 (Reactome) | ||
| PPi | Arrow | R-HSA-5696816 (Reactome) | ||
| Pi | Arrow | R-HSA-6783483 (Reactome) | ||
| R-HSA-5696807 (Reactome) | TRNT1 (CCA-adding enzyme) polymerizes the non-templated nucleotides CCA onto the 3' end (acceptor arm) of tRNAs (Reichert et al. 2001, Lizano et al. 2007, Lizano et al. 2008). In contrast to some eubacterial tRNA genes, eukaryotic tRNA genes do not encode CCA at the 3' end. The added CCA sequence is determined by the structural properties of the TRNT1 protein itself rather than by any nucleic acid template (Augustin et al. 2003, Ernst et al. 2015, Kuhn et al. 2015, see also the structure of the bacterial enzyme in Li et al. 2002). After polymerization of a single CCA motif, conformational change of the enzyme ejects the tRNA before additional nucleotides can be polymerized (Kuhn et al. 2015). Aberrant RNA with two CCA motifs is targeted for destruction. | |||
| R-HSA-5696810 (Reactome) | The RNase P RNA-protein complex located in the nucleus endonucleolytically cleaves near the 5' end of pre-tRNAs, generating the mature 5' end (Ferrari et al. 1980, Bartkiewicz et al. 1989, Jiang et al. 2001, Reiner et al. 2011, reviewed in Jarrous 2002). The site of cleavage is determined by the length of the helices in the acceptor and T stems of the tRNA (Yuan and Altman 1995). Human cells contain distinct nuclear and mitochondrial RNase P activities (Rossmanith et al. 1995), with nuclear RNase P localized in the nucleolus (Jarrous et al. 1999). The nuclear RNase P is similar to bacterial enzymes in having a catalytic RNA component. The mitochondrial RNase P is unusual in containing only protein subunits (Holzmann et al. 2008). | |||
| R-HSA-5696813 (Reactome) | The TSEN complex endonucleolytically cleaves 5' and 3' of introns in tRNAs, leaving a 2',3' cyclic phosphate on the 5' exon and a 5' hydroxyl on the 3' exon (Paushkin et al. 2004, Trotta et al. 2006). | |||
| R-HSA-5696815 (Reactome) | ELAC2, a RNaseZ activity in humans, endonucleolytically cleaves pre-tRNAs near the 3' end, generating a 3' hydroxyl group to which the nucleotides CCA will be polymerized (Takaku et al. 2004, Yan et al. 2006, Elbarbary et al. 2008). ELAC2 is located in both the nucleus and mitochondria (Brzezniak et al. 2011). ELAC1, a homologue of ELAC2, is located in the cytosol (Rossmanith 2011) and cleaves 3' ends of tRNAs in vitro (Takaku et al. 2003). | |||
| R-HSA-5696816 (Reactome) | The RNA ligase complex ligates tRNA exons yielding intact, spliced tRNAs (Popow et al. 2011, Popow et al. 2014). The reaction apparently occurs in one step with no residual 2' phosphate that requires removal, as in yeast. | |||
| R-HSA-6783483 (Reactome) | The nuclear export receptor XPOT (Exportin-t) interacts with both tRNA (Li and Sprinzl 2006) and RAN:GTP and the complex is translocated from the nucleus to the cytosol through the nuclear pore (Arts et al. 1998, Kutay et al. 1998, Kuersten et al. 2002, reviewed in Leisegang et al. 2012). RAN:GTP-dependent interactions of XPOT with components of the nuclear pore may increase the efficiency of the transport cycle (Kuersten et al. 2002). | |||
| R-HSA-6785478 (Reactome) | XPOT binds processed tRNA together with RAN:GTP in the nucleus (Arts et al. 1998, Kutay et al. 1998, Li and Sprinzl 2006). | |||
| RNase P | mim-catalysis | R-HSA-5696810 (Reactome) | ||
| Ran-GTP | R-HSA-6785478 (Reactome) | |||
| Ran:GDP | Arrow | R-HSA-6783483 (Reactome) | ||
| Spliced tRNA with 3' CCA | Arrow | R-HSA-5696816 (Reactome) | ||
| TRNT1 | mim-catalysis | R-HSA-5696807 (Reactome) | ||
| TSEN complex | mim-catalysis | R-HSA-5696813 (Reactome) | ||
| XPOT | Arrow | R-HSA-6783483 (Reactome) | ||
| XPOT | R-HSA-6785478 (Reactome) | |||
| pre-tRNA | R-HSA-5696810 (Reactome) | |||
| tRNA intron | Arrow | R-HSA-5696813 (Reactome) | ||
| tRNA ligase complex | mim-catalysis | R-HSA-5696816 (Reactome) | ||
| tRNA:XPOT:RAN:GTP | Arrow | R-HSA-6785478 (Reactome) | ||
| tRNA:XPOT:RAN:GTP | R-HSA-6783483 (Reactome) | |||
| tRNA | Arrow | R-HSA-6783483 (Reactome) | ||
| tRNA | R-HSA-6785478 (Reactome) |
