Translation: The long and short of it

Longer poly(A) tails improve translation in early development, but not in mature cells that have higher levels of the protein PABPC.
  • Download
  • Cite
  • CommentOpen annotations (there are currently 0 annotations on this page).
  1. Lori A Passmore  Is a corresponding author
  2. Terence TL Tang
  1. MRC Laboratory of Molecular Biology, United Kingdom

The genetic code stored in DNA provides cells with the blueprint they need to make proteins. The relevant gene is first transcribed into an intermediate molecule called mRNA (short for messenger RNA), which in turn gets translated by large cellular machines called ribosomes into the string of amino acids that make up a protein. At the end of each mRNA molecule is a poly(A) tail comprised of tens to hundreds of nucleotides called adenosines. The length of these tails can vary greatly between different mRNAs, and longer poly(A) tails are thought to improve translation and increase mRNA stability (Sachs, 1990).

Poly(A) tails stimulate the process of translation through a protein called PABPC (short for Poly(A)-Binding Protein, Cytoplasmic), which binds to the tail (Kühn and Wahle, 2004). This led to the assumption that mRNA molecules with longer tails are translated more efficiently (meaning they produce more proteins) because they can be bound by more copies of PABPC.

However, decades of research on the poly(A) tail have led to inconsistent results: in some experiments, longer poly(A) tails improve translation as hypothesized, while in others they have no effect (Beilharz and Preiss, 2007; Legnini et al., 2019; Lim et al., 2016; Lima et al., 2017; Morgan et al., 2017; Nudel et al., 1976; Subtelny et al., 2014). The contentious role of PABPC in translation efficiency has raised fundamental questions: exactly how important are the poly(A) tail and PABPC in translation, and what are their relative roles in different types of cell? Now, in eLife, David P Bartel and Kehui Xiang from the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology report new findings that help to answer these questions (Xiang and Bartel, 2021).

To investigate the role PABPC and poly(A) tail length play in translation efficiency, Xiang and Bartel manipulated PABPC levels in Xenopus oocytes and in post-embryonic mammalian cells. They then measured the length of the poly(A) tails and compared this to the number of ribosomes occupying each mRNA molecule, which acts as a readout for translation efficiency.

Xiang and Bartel discovered that poly(A) tail length is only linked to translation efficiency when certain criteria are met (Figure 1). They found that when PABPC concentrations were increased in oocytes, mRNAs with shorter poly(A) tails would bind to more ribosomes and show improved translation, whereas those with longer tails were unaffected. Therefore, the first criterion is that PABPC concentrations must be limiting for the protein to preferentially bind to mRNAs with longer poly(A) tails and enhance their translation. Second, for this coupling to occur, mRNA molecules not bound by PABPC must be protected from degradation. Finally, the higher number of PABPC proteins connected to the longer tails must help ribosomes load onto the mRNA molecule more efficiently to increase the amount of protein each mRNA can produce.

The role PABPC and poly(A) tail length play in translation efficiency changes during development.

During early development (left), the amount of PABPC (grey) is limiting. As a result, most of the PABPC available binds to messenger RNAs (mRNAs; orange) with longer poly(A) tails, which helps …

In oocytes and early embryos, all three of these conditions are met. This suggests that, during the early stages of development, coupling between poly(A) tail length and translation efficiency plays a primary role in gene expression. However, the relative amount of PABPC protein greatly increases as development progresses, and it eventually occupies every accessible poly(A) tail. Since every mRNA with a poly(A) tail is bound to at least one PABPC, translation no longer depends on the length of the tail, and it is likely that additional factors determine translation efficiency. In this situation, PABPC takes on a new role and instead protects mRNA molecules from destruction, particularly those with shorter poly(A) tails (Figure 1). Its role in stabilising mRNAs could be significant as many ‘housekeeping’ genes, whose expression is required for normal cellular function, tend to have shorter poly(A) tails (Lima et al., 2017).

With exhaustive experiments in different cell types and cellular conditions, Xiang and Bartel firmly establish that the roles of PABPC and poly(A) are highly context-dependent. These results reconcile many years of controversy, by demonstrating that PABPC and the poly(A) tail play different roles in different situations: during the early stages of development, poly(A) tail length and translation efficiency are coupled together by PABPC, while later in development, this relationship is lost and PABPC instead promotes mRNA stability.

Future studies can build upon this foundation by studying how mRNAs with shorter poly(A) tails are stabilised during early development, or which additional factors regulate translation efficiency in mature cells. Furthermore, it remains a mystery how the transition between early and late development is sensed and regulated, leading to a dramatic increase in PABPC levels. Finally, this study raises the interesting possibility that certain cell types, organisms, or cellular conditions exploit the dynamic relationship between PABPC abundance and poly(A) tail length to fine tune gene expression.

References

    1. Kühn U
    2. Wahle E
    (2004) Structure and function of poly(A) binding proteins
    Biochimica Et Biophysica Acta (BBA) - Gene Structure and Expression 1678:67–84.
    https://doi.org/10.1016/j.bbaexp.2004.03.008

Article and author information

Author details

  1. Lori A Passmore

    Lori A Passmore is at the MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

    For correspondence
    passmore@mrc-lmb.cam.ac.uk
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1815-3710
  2. Terence TL Tang

    Terence TL Tang is at the MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7802-0461

Publication history

  1. Version of Record published:

Copyright

© 2021, Passmore and Tang

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,259
    views
  • 245
    downloads
  • 11
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

Further reading

    1. Chromosomes and Gene Expression
    2. Evolutionary Biology
    Gülnihal Kavaklioglu, Alexandra Podhornik ... Christian Seiser
    Research Article

    Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.

    1. Chromosomes and Gene Expression
    Shihui Chen, Carolyn Marie Phillips
    Research Article

    RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized during Caenorhabditis elegans embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.