The oxidoreductase PYROXD1 uses NAD(P)+ as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response

Asanović, Igor; Strandback, Emilia Sofia; Kroupova, Alena; Pasajlic, Djurdja; Meinhart, Anton; Pai, Tsung-Pin; Djoković, Nemanja; Anrather, Dorothea; Schuetz, Thomas; Suskiewicz, Marcin; Sillamaa, Sirelin; Köcher, Thomas; Beveridge, Rebecca; Nikolic, Katarina; Schleiffer, Alexander; Jínek, Martin; Hartl, Markus; Clausen, Tim; Penninger, Josef; Macheroux, Peter; Weitzer, Stefan; Martı́nez, Javier

doi:10.1016/j.molcel.2021.04.007

Cited by 25 publications

(48 citation statements)

References 77 publications

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“…Additional structural studies of intermediate catalytic states and different metal ion-bound complexes will thus be needed to uncover whether the observed plasticity of metal ion coordination in RtcB active site plays a role in the catalytic mechanism. Finally, both RTCB and the entire tRNA-LC were recently shown to be redox-regulated and to undergo oxidative inactivation in the presence of copper, suggesting that the binding of copper ions in the active site promotes oxidation of the active site cysteine (Cys122 RTCB ), thus precluding proper divalent metal coordination ( Asanović et al, 2021 ). The NAD(P)H-dependent interaction of RTCB with PYROXD1 counteracts this process ( Asanović et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, both RTCB and the entire tRNA-LC were recently shown to be redox-regulated and to undergo oxidative inactivation in the presence of copper, suggesting that the binding of copper ions in the active site promotes oxidation of the active site cysteine (Cys122 RTCB ), thus precluding proper divalent metal coordination ( Asanović et al, 2021 ). The NAD(P)H-dependent interaction of RTCB with PYROXD1 counteracts this process ( Asanović et al, 2021 ). However, the precise chemical mechanism by which PYROXD1 protects RTCB is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

“…This is thought to involve a conserved metal binding site in Archease that might influence the positioning of the divalent metal cations in the active site of RtcB ( Desai et al, 2015 ). The catalytic activity of human RTCB was recently shown to be sensitive to copper-mediated oxidative inactivation under aerobic conditions ( Asanović et al, 2021 ). The inactivation is counteracted by the oxidoreductase PYROXD1, which protects the active site of RTCB by forming a complex with RTCB in the presence of NAD(P)H ( Asanović et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…The catalytic activity of human RTCB was recently shown to be sensitive to copper-mediated oxidative inactivation under aerobic conditions ( Asanović et al, 2021 ). The inactivation is counteracted by the oxidoreductase PYROXD1, which protects the active site of RTCB by forming a complex with RTCB in the presence of NAD(P)H ( Asanović et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Molecular architecture of the human tRNA ligase complex

Kroupova

Ackle

Asanović

et al. 2021

eLife

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RtcB enzymes are RNA ligases that play essential roles in tRNA splicing, unfolded protein response, and RNA repair. In metazoa, RtcB functions as part of a five-subunit tRNA ligase complex (tRNA-LC) along with Ddx1, Cgi-99, Fam98B and Ashwin. The human tRNA-LC or its individual subunits have been implicated in additional cellular processes including microRNA maturation, viral replication, DNA double-strand break repair and mRNA transport. Here we present a biochemical analysis of the inter-subunit interactions within the human tRNA-LC along with crystal structures of the catalytic subunit RTCB and the N-terminal domain of CGI-99. We show that the core of the human tRNA-LC is assembled from RTCB and the C-terminal alpha-helical regions of DDX1, CGI-99, and FAM98B, all of which are required for complex integrity. The N-terminal domain of CGI-99 displays structural homology to calponin-homology domains, and CGI-99 and FAM98B associate via their N-terminal domains to form a stable subcomplex. The crystal structure of GMP-bound RTCB reveals divalent metal coordination geometry in the active site, providing insights into its catalytic mechanism. Collectively, these findings shed light on the molecular architecture and mechanism of the human tRNA ligase complex, and provide a structural framework for understanding its functions in cellular RNA metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular architecture of the human tRNA ligase complex

Kroupova

Ackle

Asanović

et al. 2021

eLife

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“…No epigenome-wide significant results could be discerned in the PD cases meta-analysis; however, two CpG-sites presented with p -values below 1.0 × 10 −05 : cg09738429 ( p = 6.40 × 10 −06 , located in an intergenic shore region in the next proximity of PYROXD1 ) and cg03341655 ( p = = 8.14 × 10 −06 , located in the exonic region of GFOD2 ). PYROXD1 is involved in the response to oxidative stress [ 27 ]. Recent studies report higher DNAm in this gene in acute coronary syndrome and brain white matter lesions in older populations [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder

et al. 2022

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Background Panic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2–3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD. Methods DNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association. Results Two CpG-sites presented with p-values below 1 × 10−05 in PD: cg09738429 (p = 6.40 × 10−06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10−06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes. Conclusion This first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.

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tRNA‐derived RNAs: Biogenesis and roles in translational control

Akiyama

Ivanov

2023

WIREs RNA

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Transfer RNA (tRNA)‐derived RNAs (tDRs) are a class of small non‐coding RNAs that play important roles in different aspects of gene expression. These ubiquitous and heterogenous RNAs, which vary across different species and cell types, are proposed to regulate various biological processes. In this review, we will discuss aspects of their biogenesis, and specifically, their contribution into translational control. We will summarize diverse roles of tDRs and the molecular mechanisms underlying their functions in the regulation of protein synthesis and their impact on related events such as stress‐induced translational reprogramming.This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs

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The oxidoreductase PYROXD1 uses NAD(P)+ as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response

Cited by 25 publications

References 77 publications

Molecular architecture of the human tRNA ligase complex

Molecular architecture of the human tRNA ligase complex

Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder

tRNA‐derived RNAs: Biogenesis and roles in translational control

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