Widespread Accumulation of Ribosome-Associated Isolated 3′ UTRs in Neuronal Cell Populations of the Aging Brain

Sudmant, Peter H.; Lee, Hyeseung; Domínguez, Daniel; Heiman, Myriam; Burge, Christopher B.

doi:10.1016/j.celrep.2018.10.094

Cited by 72 publications

(71 citation statements)

References 49 publications

(83 reference statements)

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“…Finally, we noted an interesting accumulation of the 3'UTR region of histone gene HIST2H2BE in both senescent and EXOSC3-depleted cells ( Figure 1K). This phenomenon was reminiscent of the accumulation of 3'UTRs previously described in the aging mouse brain (11).…”

Section: Reduced Rna Turnover In Senescent Cellssupporting

confidence: 59%

“…Some observations are suggestive of a more comprehensive impact of RNAs in cellular senescence, via their production, their maturation, or their turn-over. For example, it was reported that in the aging mouse brain, some neurons start accumulating 3′ untranslated regions (UTRs), resulting in the production of small peptides of yet unknown function (11). In parallel, transcripts from SINEs/Alus, a family of repetitive elements particularly abundant in euchromatin, have been reported to accumulate in senescent cells with an impact on genome integrity (12).…”

Section: Introductionmentioning

confidence: 99%

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Reduced RNA turnover as a driver of cellular senescence

Mullani

Porozhan

Batsché

et al. 2019

Preprint

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Accumulation of senescent cells is an important contributor to chronic inflammation upon aging. While cytoplasmic DNA was shown to drive the inflammatory phenotype of senescent cells, an equivalent role for RNA has never been explored. Here, we show that cellular senescence correlates with reduced expression of RNA exosome subunits and coincident accumulation of promoter RNAs and immature RNA transcripts. Forced accumulation of these RNAs by inactivation of the Exosc3 exosome subunit induces expression of senescence markers and reduced mitochondrial gene expression. Reciprocally, mitochondrial suffering and oxidative stress results in reduced RNA decay, suggestive of a feedback loop between RNA decay and mitochondrial activity. As several of the accumulating RNAs are also produced during normal activation of immune cells and contain Alu sequences known to trigger an innate immune response, we propose that stabilizing immature and unstable RNAs participate in driving and maintaining the permanent inflammatory state characteristic of cellular senescence.

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Section: Reduced Rna Turnover In Senescent Cellssupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Reduced RNA turnover as a driver of cellular senescence

Mullani

Porozhan

Batsché

et al. 2019

Preprint

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“…Proteasome activity is further reduced in the old brain, correlating with an increased imbalance between the 19S and 20S complexes with time ( Figure 5B and 5C). In addition, altered stoichiometry of the ribosome can underlie both the reduction and the qualitative changes of protein synthesis in brain aging (Ori et al, 2015;Schimanski and 5 Barnes, 2010; Sudmant et al, 2018). An alteration of the stoichiometry between membranebound and cytosolic components of the lysosomal v-type ATPase ( Figure 2F) might influence the acidification of lysosomes and the activation of mTORC1 (Zoncu et al, 2011), thus hampering the clearance of protein aggregates.…”

mentioning

confidence: 99%

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

Sacramento

Kirkpatrick

Mazzetto

et al. 2019

Preprint

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A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging by using the short-lived vertebrate Nothobranchius furzeri and combining transcriptomics, proteomics and thermal proteome profiling. We found that the 25 correlation between protein and mRNA levels is progressively reduced during aging, and that post-transcriptional mechanisms are responsible for over 40% of these alterations. These changes induce a progressive stoichiometry loss in protein complexes, including ribosomes, which have low thermal stability in brain lysates and whose component proteins are enriched in aggregates found in old brains. Mechanistically, we show that reduced proteasome activity occurs early 30 during brain aging, and is sufficient to induce loss of stoichiometry. Our work thus defines early events in the aging process that can be targeted to prevent loss of protein homeostasis and agerelated neurodegeneration.

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“…However, this overall slight reduction in protein synthesis is unlikely to account for the selective inhibition of NMD on a fraction of the NMD targets, and moreover the puromycylation assay does not address which step of translation is affected by ABCE1 KD. There is evidence that ABCE1 depletion causes ribosome stalling at termination codon and an increased ribosome occupancy in the 3'UTR, suggesting mainly an impairment of translation termination (Mills et al, 2016;Sudmant et al, 2018;Young et al, 2015). According to this model, mRNAs are expected to still be associated with polysomes upon ABCE1 KD, and strong association of mRNAs with polysomes would provide indirect evidence that these mRNAs are still actively translated.…”

Section: Nmd Sensitive Mrnas Are Strongly Associated With Polysomes Imentioning

confidence: 99%

Ribosome recycling factor ABCE1 depletion inhibits nonsense-mediated mRNA decay by promoting stop codon readthrough

Annibaldis

Dreos

Domanski

et al. 2019

Preprint

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Highlights• ABCE1 knockdown suppresses NMD of many NMD-sensitive mRNAs• The observed NMD inhibition occurs at a stage prior to SMG6-mediated cleavage of the mRNA • ABCE1 depletion enhances ribosome occupancy at stop codons and in the 3' UTR• ABCE1 depletion enhances readthrough of the stop codon• Enhanced readthrough inhibits NMD, presumably by clearing the 3' UTR of NMD factors SUMMARY Nonsense-mediated mRNA decay (NMD) is an essential post-transcriptional surveillance pathway in vertebrates that appears to be mechanistically linked with translation termination. To gain more insight into this connection, we interfered with translation termination by depleting human cells of the ribosome recycling factor ABCE1, which resulted in an upregulation of many but not all endogenous NMD-sensitive mRNAs. Notably, the suppression of NMD on these mRNAs occurs at a step prior to their SMG6-mediated endonucleolytic cleavage. Ribosome profiling revealed that ABCE1 depletion results in ribosome stalling at stop codons and increased ribosome occupancy in 3' UTRs, indicative of enhanced stop codon readthrough or re-initiation. Using reporter genes, we further demonstrate that the absence of ABCE1 indeed increases the rate of readthrough, which would explain the observed NMD inhibition, since enhanced readthrough has been previously shown to render NMD-sensitive transcripts resistant to NMD by displacing NMD triggering factors like UPF1 and exon junction complexes (EJCs) from the 3' UTR. Collectively, our results show that improper ribosome disassembly interferes with proper NMD activation.indicates that NMD ensues when a ribosome stalls at a termination codon (TC) for prolonged time because of a failure to properly or fast enough terminate translation (Amrani et al., 2004;Peixeiro et al., 2011). On mRNA with problems in translation termination, the so-called SURF complex (composed of SMG1, UPF1 and the release factors eRF1 and eRF3) was proposed to assemble at the TC (Ivanov et al., 2008;Kashima et al., 2006;Singh et al., 2008). SMG1-mediated phosphorylation of UPF1, a core factor of NMD, appears to be a key event in activating NMD, because hyper-phosphorylated UPF1 subsequently serves as a binding platform for the heterodimer SMG5/SMG7 and for the endonuclease SMG6, allowing for two different decay routes (Muhlemann and Lykke-Andersen, 2010). A third decay pathway operating via SMG5 and PNRC2 has also been proposed (Cho et al., 2013) but remains controversial (Loh et al., 2013;Nicholson et al., 2018). Moreover, a recent study challenged the SURF complex-based NMD activation model by showing that UPF3B rather than UPF1 interacts with the release factors (Neu-Yilik et al.

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Widespread Accumulation of Ribosome-Associated Isolated 3′ UTRs in Neuronal Cell Populations of the Aging Brain

Cited by 72 publications

References 49 publications

Reduced RNA turnover as a driver of cellular senescence

Reduced RNA turnover as a driver of cellular senescence

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

Ribosome recycling factor ABCE1 depletion inhibits nonsense-mediated mRNA decay by promoting stop codon readthrough

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