Short poly(A) tails are protected from deadenylation by the LARP1–PABP complex

Park, Joha; Kim, Myeonghwan; Yi, Hyerim; Baeg, Kyungmin; Choi, Yu-Sung; Lee, Young-suk; Lim, Ju Young; Kim, V. Narry

doi:10.1038/s41594-023-00930-y

Cited by 10 publications

(16 citation statements)

References 71 publications

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“…In addition to its role in 5′TOP translational repression, LARP1 has been reported to protect mRNAs from degradation ( 20 , 21 , 26 , 38 , 39 ). It is now unclear whether this protective role of LARP1 is restricted to 5′TOP mRNAs, TOP-like mRNAs, or affects all mRNAs ( 37 ).…”

Section: Resultsmentioning

confidence: 99%

“…Other RNA: abs log 2 FC ≥ 0.5 P val ≥ 5 show a highly selective destabilization of nearly all 5′TOP mRNAs upon loss of LARP1, with virtually all other mRNAs being largely unaffected. Similarly, a recent study found that loss of LARP1 resulted in rapid deadenylation of short polyA tails of all mRNAs, with 5′TOP mRNAs being more affected than other types of mRNAs (26). It is possible that differences in LARP1 depletion or measurement of mRNA stability or polyA-tail length may account for the differences in specificity for 5′TOP mRNAs between the studies.…”

Section: ′Top Mrnamentioning

confidence: 93%

“…Crosslinking studies have found LARP1 associates with thousands of mRNAs including 5′TOP mRNAs, and a subset of these transcripts have increased binding upon mTORC1 inhibition ( 7 , 24 , 25 ). In contrast, polyA tail sequencing in mTOR active cells has found LARP1 to inhibit mRNA deadenylation globally but that 5′TOP transcripts were among the most strongly affected transcripts upon LARP1 depletion ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

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Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5′TOP mRNAs

Hochstoeger,

Papasaikas,

Piskadlo

et al. 2024

Sci. Adv.

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A central mechanism of mTOR complex 1 (mTORC1) signaling is the coordinated translation of ribosomal protein and translation factor mRNAs mediated by the 5′-terminal oligopyrimidine motif (5′TOP). Recently, La-related protein 1 (LARP1) was proposed to be the specific regulator of 5′TOP mRNA translation downstream of mTORC1, while eIF4E-binding proteins (4EBP1/2) were suggested to have a general role in translational repression of all transcripts. Here, we use single-molecule translation site imaging of 5′TOP and canonical mRNAs to study the translation of single mRNAs in living cells. Our data reveal that 4EBP1/2 has a dominant role in repression of translation of both 5′TOP and canonical mRNAs during pharmacological inhibition of mTOR. In contrast, we find that LARP1 selectively protects 5′TOP mRNAs from degradation in a transcriptome-wide analysis of mRNA half-lives. Our results clarify the roles of 4EBP1/2 and LARP1 in regulating 5′TOP mRNAs and provide a framework to further study how these factors control cell growth during development and disease.

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Section: Resultsmentioning

confidence: 99%

Section: ′Top Mrnamentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5′TOP mRNAs

Hochstoeger,

Papasaikas,

Piskadlo

et al. 2024

Sci. Adv.

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“…Normal mRNAs emerge from the nucleus with long and heterogeneous poly(A) tails, and subsequently experience a rapid period of deadenylation (Eisen et al 2020; Sawicki et al 1977; Tudek et al 2021). Normal mRNAs can also experience a more variable (and often much slower) deadenylation over their lifetime that is associated with translation (Eisen et al 2020; Yi et al 2018; Tudek et al 2021; Park et al 2023). NMD targets are only recognized as such during translation, predicting that PTC-containing nascent mRNAs will also experience the initial period of deadenylation.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the understanding of poly(A) tails, deadenylation, and decapping in normal (non-PTC-containing) mRNA metabolism improved over the last several years (reviewed in (Zhang et al 2023)). Contemporary studies suggest that deadenylation is a part of normal mRNA maturation as well as normal mRNA decay (Chang et al 2014; Lima et al 2017; Yi et al 2018; Eisen et al 2020; Alles et al 2023; Park et al 2023; Tudek et al 2021). Nascent mRNAs have a long poly(A) tail that is partially deadenylated to a ∼30-70 poly(A) tail as the mRNA matures.…”

Section: Introductionmentioning

confidence: 99%

NMD targets experience deadenylation during their maturation and endonucleolytic cleavage during their decay

Viscardi,

Arribere

2023

Preprint

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Premature stop codon-containing mRNAs can produce truncated and dominantly acting proteins that harm cells. Eukaryotic cells protect themselves by degrading such mRNAs via the Nonsense-Mediated mRNA Decay (NMD) pathway. The precise reactions by which cells attack NMD target mRNAs remain obscure, precluding a mechanistic understanding of NMD and hampering therapeutic efforts to control NMD. A key step in NMD is the decay of the mRNA, which is proposed to occur via several competing models including deadenylation, exonucleolytic decay, and/or endonucleolytic decay. We set out to clarify the relative contributions of these decay mechanisms to NMD, and to identify the role of key factors. Here, we modify and deploy single-molecule nanopore mRNA sequencing to capture full-length NMD targets and their degradation intermediates, and we obtain single-molecule measures of splicing isoform, cleavage state, and poly(A) tail length. We observe robust endonucleolytic cleavage of NMD targetsin vivothat depends on the nuclease SMG-6 and we use the occurence of cleavages to identify several known NMD targets. We show that NMD target mRNAs experience deadenylation, but similar to the extent that normal mRNAs experience as they enter the translational pool. Furthermore, we show that a factor (SMG-5) that historically was ascribed a function in deadenylation, is in fact required for SMG-6-mediated cleavage. Our results support a model in which NMD factors act in concert to degrade NMD targets in animals via an endonucleolytic cleavage near the stop codon, and suggest that deadenylation is a normal part of mRNA (and NMD target) maturation rather than a facet unique to NMD. Our work clarifies the route by which NMD target mRNAs are attacked in an animal.

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Nano3′RACE: A Method to Analyze Poly(A) Tail Length and Nucleotide Additions at the 3′ Extremity of Selected mRNAs Using Nanopore Sequencing

Giraudo,

Simonnot,

Pflieger

et al. 2023

Methods in Molecular Biology

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Short poly(A) tails are protected from deadenylation by the LARP1–PABP complex

Cited by 10 publications

References 71 publications

Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5′TOP mRNAs

Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5′TOP mRNAs

NMD targets experience deadenylation during their maturation and endonucleolytic cleavage during their decay

Nano3′RACE: A Method to Analyze Poly(A) Tail Length and Nucleotide Additions at the 3′ Extremity of Selected mRNAs Using Nanopore Sequencing

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