Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

Cherry, Patrick D.; Peach, Sally E.; Hesselberth, Jay R.

doi:10.7554/elife.42262

Cited by 24 publications

(19 citation statements)

References 49 publications

(74 reference statements)

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“…At this step, the tRNA fragments would be in competition among three different fates: completion of endonucleolytic cleavage by the SEN complex; healing and religation by the tRNA ligase (Trl1); or decay by exonucleases. This type of model was recently proposed as a mechanism regulating decay of HAC1 mRNA, encoding a major regulator of the unfolded protein response; this mRNA is spliced by a similar mechanism to tRNA, using Ire1 endonuclease and tRNA ligase (Sidrauski et al 1996;Sidrauski and Walter 1997), and ligation of its cleavage products is in competition with decay mediated by Xrn1 (Cherry et al 2019;Peschek and Walter 2019). Future experiments should cast light on the mechanism by which the MPD pathway monitors pre-tRNA quality and mediates decay.…”

Section: Discussionmentioning

confidence: 99%

Mutations in the anticodon stem of tRNA cause accumulation and Met22-dependent decay of pre-tRNA in yeast

Payea

Hauke

Zoysa

et al. 2019

RNA

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During tRNA maturation in yeast, aberrant pre-tRNAs are targeted for 3 ′ ′ ′ ′ ′ -5 ′ ′ ′ ′ ′ degradation by the nuclear surveillance pathway, and aberrant mature tRNAs are targeted for 5 ′ ′ ′ ′ ′ -3 ′ ′ ′ ′ ′ degradation by the rapid tRNA decay (RTD) pathway. RTD is catalyzed by the 5 ′ ′ ′ ′ ′ -3 ′ ′ ′ ′ ′ exonucleases Xrn1 and Rat1, which act on tRNAs with an exposed 5 ′ ′ ′ ′ ′ end due to the lack of certain body modifications or the presence of destabilizing mutations in the acceptor stem, T-stem, or tRNA fold. RTD is inhibited by mutation of MET22, likely due to accumulation of the Met22 substrate adenosine 3 ′ ′ ′ ′ ′ ,5 ′ ′ ′ ′ ′ bis-phosphate, which inhibits 5 ′ ′ ′ ′ ′ -3 ′ ′ ′ ′ ′ exonucleases. Here we provide evidence for a new tRNA quality control pathway in which intron-containing pre-tRNAs with destabilizing mutations in the anticodon stem are targeted for Met22-dependent pre-tRNA decay (MPD). Multiple SUP4 οc anticodon stem variants that are subject to MPD each perturb the bulge-helix-bulge structure formed by the anticodon stem-loop and intron, which is important for splicing, resulting in substantial accumulation of end-matured unspliced pre-tRNA as well as pre-tRNA decay. Mutations that restore exon-intron structure commensurately reduce pre-tRNA accumulation and MPD. The MPD pathway can contribute substantially to decay of anticodon stem variants, since pre-tRNA decay is largely suppressed by removal of the intron or by restoration of exon-intron structure, each also resulting in increased tRNA levels. The MPD pathway is general as it extends to variants of tRNA Tyr(GUA) and tRNA Ser(CGA) . These results demonstrate that the integrity of the anticodon stem-loop and the efficiency of tRNA splicing are monitored by a quality control pathway.

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Section: Discussionmentioning

confidence: 99%

Mutations in the anticodon stem of tRNA cause accumulation and Met22-dependent decay of pre-tRNA in yeast

Payea

Hauke

Zoysa

et al. 2019

RNA

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“… 45 Xrn1 can also activate the translation, transcription, and decay of the specific mRNAs, and these functions are all linked to each other by Xrn1 for a specific group of mRNAs encoding membrane proteins. 46 The hydrophobic domains of these membrane proteins have the tendency to form aggregates. To prevent the aggregation of these proteins which might be toxic, their expression and localization should be strictly controlled.…”

Section: Discussionmentioning

confidence: 99%

Global Gene Expression Regulation Mediated by TGFβ Through H3K9me3 Mark

2022

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Background: Epigenetic alterations play an important part in carcinogenesis. Different biological responses, including cell proliferation, migration, apoptosis, invasion, and senescence, are affected by epigenetic alterations in cancer. In addition, growth factors, such as transforming growth factor beta (TGFβ) are important regulators of tumorigenesis. Our understanding of the interplay between the epigenetic bases of tumorigenesis and growth factor signaling in tumorigenesis is rudimentary. Some studies suggest a link between TGFβ signaling and the heterochromatinizing histone mark H3K9me3. There is evidence for signal-dependent interactions between R-Smads and histone methyltransferases. However, the effects of TGFβ signaling on genome wide H3K9me3 landscape remains unknown. Our research examines TGFβ -induced genome-wide H3K9me3 in prostate cancer. Method: Chromatin-Immunoprecipitation followed by sequencing was performed to analyze genome-wide association of H3K9me3 epigenetic mark. DAVID Functional annotation tool was utilized to understand the involvement of different Biological Processes and Molecular Function. MEME-ChIP tool was also used to analyze known and novel DNA-binding motifs. Results: H3K9me3 occupancy appears to increase at intronic regions after short-term (6 hours) TGFβ stimulation and at distal intergenic regions during long-term stimulation (24 hours). We also found evidence for a possible association of SLC transporters with H3K9me3 mark in presence of TGFβ during tumorigenesis. No direct correlation was found between the occupancy of H3K9me3 mark and the expression of various genes. The epigenetic mechanisms-mediated regulation of gene expression by TGFβ was concentrated at promoters rich in SRY and FOXJ3 binding sites. Conclusion: Our results point toward a positive association of oncogenic function of TGFβ and the H3K9me3 mark and provide a context to the role of H3K9me3 in TGFβ-induced cell migration and cell adhesion. Interestingly, these functions of TGFβ through H3K9me3 mark regulation seem to depend on transcriptional activation in contrast to the conventionally known repressive nature of H3K9me3.

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“…The exon halves are then ligated together during the sealing step, by Trl1's RNA ligase domain. Beyond tRNA splicing, RTCB and Trl1 have been shown to function in other RNA processing pathways such as mRNA splicing during the unfolded protein response (Cherry et al, 2019;Kosmaczewski et al, 2014;Peschek & Walter, 2019). While RTCB and Trl1 have been shown to function in other RNA processing pathways, little is known about what role the TSEN complex plays in processing RNAs beyond intron-containing pre-tRNAs.…”

Section: Overview Of Transfer Rna Splicing In Eukaryotesmentioning

confidence: 99%

Recent insights into the structure, function, and regulation of the eukaryotic transfer RNA splicing endonuclease complex

2022

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The splicing of transfer RNA (tRNA) introns is a critical step of tRNA maturation, for intron-containing tRNAs. In eukaryotes, tRNA splicing is a multi-step process that relies on several RNA processing enzymes to facilitate intron removal and exon ligation. Splicing is initiated by the tRNA splicing endonuclease (TSEN) complex which catalyzes the excision of the intron through its two nuclease subunits. Mutations in all four subunits of the TSEN complex are linked to a family of neurodegenerative and neurodevelopmental diseases known as pontocerebellar hypoplasia (PCH). Recent studies provide molecular insights into the structure, function, and regulation of the eukaryotic TSEN complex and are beginning to illuminate how mutations in the TSEN complex lead to neurodegenerative disease. Using new advancements in the prediction of protein structure, we created a three-dimensional model of the human TSEN complex. We review functions of the TSEN complex beyond tRNA splicing by highlighting recently identified substrates of the eukaryotic TSEN complex and discuss mechanisms for the regulation of tRNA splicing, by enzymes that modify cleaved tRNA exons and introns. Finally, we review recent biochemical and animal models that have worked to address the mechanisms that drive PCH and synthesize these studies with previous studies to try to better understand PCH pathogenesis.

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Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

Cited by 24 publications

References 49 publications

Mutations in the anticodon stem of tRNA cause accumulation and Met22-dependent decay of pre-tRNA in yeast

Mutations in the anticodon stem of tRNA cause accumulation and Met22-dependent decay of pre-tRNA in yeast

Global Gene Expression Regulation Mediated by TGFβ Through H3K9me3 Mark

Recent insights into the structure, function, and regulation of the eukaryotic transfer RNA splicing endonuclease complex

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