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Details on Person Features such as damaged nucleotides, strong secondary struc...
| Class:Id | Summation:9949641 |
|---|---|
| _displayName | Features such as damaged nucleotides, strong secondary struc... |
| _timestamp | 2025-11-07 01:20:14 |
| created | [InstanceEdit:9949637] May, Bruce, 2025-05-23 |
| modified | [InstanceEdit:9953251] May, Bruce, 2025-05-30 [InstanceEdit:9955884] May, Bruce, 2025-06-12 [InstanceEdit:9956297] May, Bruce, 2025-06-12 [InstanceEdit:9956749] May, Bruce, 2025-06-13 [InstanceEdit:9956788] May, Bruce, 2025-06-13 [InstanceEdit:9956791] May, Bruce, 2025-06-13 [InstanceEdit:9956848] May, Bruce, 2025-06-14 [InstanceEdit:9956849] May, Bruce, 2025-06-15 [InstanceEdit:9960458] May, Bruce, 2025-07-12 [InstanceEdit:9962782] May, Bruce, 2025-08-09 [InstanceEdit:9971549] May, Bruce, 2025-11-07 |
| text | Features such as damaged nucleotides, strong secondary structure, presence of stretches of more than four uninterrupted AAA codons in a mRNA coding region (designated a no-go mRNA) or the absence of a stop codon in a mRNA (a non-stop mRNA) can cause a ribosome to stall during translation and the stalled ribosome can cause collisions with trailing ribosomes on the mRNA (reviewed in Joazeiro 2017, Eisenack and Trentini 2022, Filbeck et al. 2022, McGirr et al. 2025). In cases in which the ribosome stalls internally on the mRNA and a 3' region of the mRNA protrudes from the ribosome, ZNF598, a ubiquitin E3 ligase that is the homolog of yeast HEL2, binds the ribosome (Garzia et al. 2017, Juszkiewicz and Hegde 2017, Sundaramoorthy et al. 2017) and catalyzes the lysine-63 (K63) linked ubiquitination of the 40S subunit ribosomal proteins eS10 (RPS10) at residues K138 and K139 and uS10 (RPS20) at residues K4 and K8 to initiate splitting of the 40S and 60S ribosomal subunits (Juszkiewicz and Hegde 2017, Sundaramoorthy et al. 2017, Garzia et al. 2017, Juszkiewicz et al. 2018, Narita et al. 2022, Miścicka et al. 2024, also inferred from yeast homologs in Matsuo et al. 2017, Sitron et al. 2017, Ikeuchi et al. 2019, reviewed in Ford et al. 2024). RACK1 then stabilizes the interface between the 40S subunits of the collided ribosomes to enable the ubiquitination of ribosomal proteins by ZNF598 (Sundaramoorthy et al. 2017). RACK1 is also required for the recruitment of EDF1 which has been proposed by structural studies to stabilize the collision interface through a conserved KKW motif and an alpha-helical segment that clamps the mRNA (Sinha et al. 2020). Additionally, EDF1 recruits the 4EHP-GIGYF2 complex to the collided ribosome to mediate translational repression of aberrant mRNAs (Sinha et al. 2020, Juszkiewicz et al. 2020), a mechanism which can also be initiated by ZNF598 (Hickey et al. 2020). The ASCC2 subunit (Narita et al. 2022) of the ribosome quality control trigger complex (ASCC, ASC-1 complex, ASCC2:ASCC3:TRIP4, homologue of the RQT complex in yeast) binds K63-linked polyubiquitin conjugated to the 40S protein uS10 (Hashimoto et al. 2020, Juszkiewicz et al. 2020, Narita et al. 2022, and inferred from yeast homologs in Matsuo et al. 2023). The ASCC3 subunit of the RQT complex splits stalled 80S ribosomes with K63-polyubiquitinated uS10 into 60S and 40S subunits (Hashimoto et al. 2020, Juszkiewicz et al. 2020, Narita et al. 2022, Miścicka et al. 2024) apparently by exerting a pulling force on the mRNA (inferred from the yeast homolog Slh1 in Best et al. 2023). The peptidyl-tRNA remains bound in the 60S subunit, with the tRNA positioned in the P site. The problematic mRNA dissociates after splitting and is thought to be degraded at this time. In the case of collided yeast ribosomes, the mRNA is first endonucleolytically cleaved and the cleavage products are exonucleolytically degraded by XRN1 and the exosome (Ikeuchi et al. 2019). Non-stop mRNAs result in ribosomal stalls proximal to the 3' end of the mRNA, which are resolved by a distinct pathway. In this case, a complex comprising PELO, a paralog of the ribosome release factor eRF1, and HBS1L:GTP, a paralog of the ribosome release factor eRF3:GTP, binds the stalled ribosome near the subunit interface and the mRNA entry site (Shao et al. 2013, and inferred from human PELO:HBS1L and rabbit ribosomes in Pisareva et al. 2011, inferred from yeast homologs DOM34:HBS1 in Shoemaker et al. 2010, Tsuboi et al. 2012, Guydosh and Green 2014, reviewed in Franckenberg et al. 2012). PELO:HBS1L preferentially acts on ribosomes that are bound to mRNAs that have fewer than 12 nucleotides extending 3' of the ribosomal P site (Pisareva et al. 2011). HBS1L hydrolyzes GTP and dissociates from PELO and the ribosome, exposing a site on PELO to which ABCE1 binds. ABCE1 then hydrolyzes ATP to cause a conformational change that splits the ribosome into 40S and 60S subunits (Shao et al. 2013, Shao and Hegde 2014, and inferred from the yeast homologs DOM34:HBS1 and archaeal homologs in Becker et al. 2012, inferred from the yeast homologs in Saito et al. 2013). ABCE1 and possibly the mRNA remain bound to the 40S ribosomal subunit, while the peptidyl-tRNA remains bound to the 60S ribosomal subunit as in the ASCC-mediated rescue pathway (Becker et al. 2012, reviewed in Franckenberg et al. 2012). At this stage of either pathway, the 40S subunit can be deubiquitinated [by OTUD3, USP21, or USP10] which may be necessary to license the 40S for further rounds of translation (Garshott et al. 2020, Meyer et al. 2020). In contrast, the 60S-peptidyl-tRNA complex requires additional steps to extract and destroy the nascent polypeptide before the 60S subunit can be recycled. NEMF (the human homolog of yeast RQC2) binds the exposed peptidyl-tRNA of the isolated 60S ribosomal subunit produced by either the RQT complex or ABCE1 and transfers alanine residues from aminoacyl tRNAs to the C-terminus of the nascent peptide, a process termed Carboxy-terminal Alanine and Threonine tailing (CAT-tailing) after the alanine and threonine tails observed in yeast (Udagawa et al. 2021, Thrun et al. 2021, inferred from the yeast homolog RQC2 in Shen et al. 2015, Kostova et al. 2017, Osuna et al. 2017). Structures of CAT-tailing intermediates in yeast indicate that RQC2 positions an aminoacyl-tRNA in the A site of the 60S subunit and eIF5A enables peptidyl transfer (Shen et al. 2015, Tesina et al. 2023). The alanine C-terminal tails are believed to push the nascent peptide through the exit tunnel of the 60S ribosomal subunit to expose lysine residues for K48-linked ubiquitination by Listerin (LTN1), however alanine tails can cause aggregation of nascent peptides (Udagawa et al. 2021, and inferred from yeast homologs in Yonashiro et al. 2016). The alanine tails can also act as degrons by binding the CRL2-KHDC10 ubiquitin E3 ligase complex (Thrun et al. 2021, Patil et al. 2023) or the RCHY1 (PIRH2) ubiquitin E3 ligase (Thrun et al. 2021, Patil et al. 2023, Wang et al. 2023) CRL2-KHDC10 and RCHY1 ubiquitinate the nascent peptide using K48 polyubiquitin linkages, targeting the nascent peptide for destruction by the 26S proteasome. Listerin (LTN1, also called RKR1 in yeast), a ubiquitin E3 ligase, is also capable of catalyzing the K48-linked ubiquitination of the nascent peptide after NEMF recruits LTN1 to the 60S ribosomal subunit (Shao et al. 2015). The N-terminal region of LTN1 contacts the 60S ribosomal subunit and NEMF while the C-terminal region of LTN1 binds the 60S ribosomal subunit near the exit tunnel (Shao et al. 2015, inferred from yeast homologs in Lyumkis et al. 2014). TCF25 (the homolog of RQC1 in yeast) interacts with LTN1 (inferred from yeast homologs in Defenouillère et al. 2013). LTN1 ubiquitinates exposed lysine residues on the nascent peptide after the residues have emerged from the exit tunnel of the 60S ribosomal subunit (Osuna et al. 2017, Kuroha et al. 2018, Abaeva et al. 2025, inferred from yeast homologs in Bengtson and Joazeiro 2010, Shao et al. 2013, Shao and Hegde 2014, reviewed in Mishra et al. 2021). TCF25, the human homolog of RQC1 in yeast, interacts with the RING domain of LTN1 to orient the ubiquitin substrate molecules to produce lysine-48 (K48) linkages in the polyubiquitin product (Kuroha et al. 2018, Abaeva et al. 2025). A hexamer of VCP subunits plus a heterodimer of UFDL1 (UFD1) and NPLOC4 bind polyubiquitin that contains lysine-48 linkages (K48polyUb) and is conjugated to the nascent peptide emerging from the exit tunnel of the 60S ribosomal subunit (Tsuchiya et al. 2017, Sato et al. 2019, Williams et al. 2023, and inferred from CDC48, the yeast orthologue of VCP, in Brandman et al. 2012, Defenouillère et al. 2013, Verma et al. 2013). In yeast, the Npl4:Ufd1 heterodimer (homolog of NPLOC4:UFD1L) acts as an adapter that binds K48-linked polyubiquitin and inserts it into the pore of the VCP hexamer (inferred from rat p97 and Ufd1:Npl4 in Meyer et al. 2000, reviewed in Meyer and van den Boom 2023). ANKZF1, which interacts with VCP, cleaves the C-terminal 3 nucleotides, CCA, of the tRNA in the peptidyl-tRNA bound to the 60S ribosomal subunit, yielding a free tRNA and the nascent peptide covalently bound to the CCA sequence (Verma et al. 2018, Yip et al. 2019, and inferred from the yeast homolog, VMS1, in Verma et al. 2018, Yip et al. 2019). In yeast, Arb1 (mammalian ABCF2) occupies the E-site of the collided ribosome, extending a domain towards the peptidyl-tRNA that may help position it for release by Vms1/ANKZF1 (SU et al. 2019). The VCP hexamer then extracts the ubiquitinated nascent peptide from the 60S ribosomal subunit. Six subunits of VCP surround the substrate protein, which is located in the central pore of the hexamer. Hydrolysis of ATP by a subunit causes it to disengage from the hexamer. Release of ADP and binding of ATP causes the subunit to rebind the hexamer more proximally to the 60S ribosomal subunit (reviewed in Meyer and van den Boom 2023). The result is a ratcheting effect that withdraws the nascent peptide from the 60S subunit. The extracted nascent peptide remains bound to the ribosome-associated quality control complex (RQC complex, LTN1:NEMF:TCF25:VCP hexamer) which dissociates from the 60S ribosomal subunit and escorts the nascent peptide to the proteasome (inferred from yeast homologs in Defenouillère et al. 2017). The region of the nascent peptide that is unfolded by the VCP hexamer is able to enter the proteasome, resulting in degradation of the nascent peptide (inferred from the yeast homolog CDC48 in Olszewski et al. 2019). After removal of the ubiquitinated nascent peptide and tRNA, and mRNA, the 60S subunit is able to be re-used in translation. The 40 S subunit is deubiquitinated by OTUD3 and USP21. |
| (summation) | [Pathway:9948299] Ribosome-associated quality control [Homo sapiens] |
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