Why are highly expressed genes transcribed with shorter Poly(A) tails?
It is difficult to make a conclusive remark about the consequences of variable lengths of the Poly-A tail for a transcript. Conventional…
It is difficult to make a conclusive remark about the consequences of variable lengths of the Poly-A tail for a transcript. Conventional knowledge, which was derived in the absence of an efficient method for sequencing the Poly(A) tails, seems to contradict the current findings, which itself has different facets.
One of the functions of the Poly(A) tail is to stabilize the mRNA by preventing its degradation by 3’→5’ exonuclease. Throughout their cytoplasmic lifetime, exonucleases constantly chew up the 3’ end, but the presence of the poly(A) tail provides RNA a window to get translated before the exonuclease eats up the coding sequence 1. Another function of the tail is to facilitate its export to the cytoplasm. This is achieved by the interaction of the tail with the Poly(A) Binding Protein (PABP).
Looking at the functions of the Poly(A) tail, an obvious conclusion would be that transcripts with no Poly(A) tail would be highly unstable (having a short half-life) and won’t be transported to the cytoplasm. But the Histone mRNA is an exception. This RNA, which also lacks introns, is the only mRNA with no Poly(A) tail. Instead, it contains a stem-loop structure at the 3’ end, which is bound by the Stem Loop Binding Protein (SLBP) that not only confers stability to the RNA but also facilitates its export to the nucleus 2.
There are a lot of ambiguous findings when we consider the case of short and long Poly(A) tail-containing RNA. Earlier, the general consensus was that short Poly(A) tail-containing transcripts would be less stable and hence should be expressed less. But advancements in tail sequencing methods have discovered that highly expressed genes contain shorter Poly(A) tails 3, 4. Hence, genes involved in regulatory functions such as those encoding transcription factors have longer Poly(A) tails, whereas genes encoding nucleosome components have shorter Poly(A) tails.
The picture becomes clearer if we consider the involvement of the Poly(A) tail with the translational machinery. Although some studies support the existence of no correlation of translational rates with the length of the Poly(A) tail 3, Lima et al. propose something called “pruning” to explain both the existence and stability of transcripts containing a shorter Poly(A) tail. Although some genes contain a Poly(A)-Limiting Element that restricts the length of the Poly(A) tail 5, for most of the transcripts (78%), completely polyadenylated versions (containing up to ~250 A’s), can be detected 4.
The Poly(A) tail is covered by PABP in the cytoplasm. PABP has been known to help in the recruitment of eIF4G for the initiation of translation. Now, the transcripts of highly expressed genes have codon optimality. High codon optimality-containing transcripts get their tail trimmed to a suitable short length containing bound PABP, and this PABP stabilizes the RNA and protects it from further deadenylation 4, 6. This is known as pruning.
But the number of bound PABP will be higher in the case of transcripts with longer tails. Still, longer tails are associated with less abundant mRNAs. This reflects the dual role of PABP. Apart from the stabilizing role, PABP has been known to recruit deadenylase factors 7. Hence, in less codon optimal transcripts, the translational machinery somehow restricts the pruning and the stabilizing effect of PABP 4, 6.
Conclusion — Hence, although the length of Poly(A) tail seems to be determining factor of stability and translation of a particular RNA, involvement of codon-optimization and translational machinery complicates our understanding in this case.
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