A Missing Post-translational Modification
Eukaryotic cells possess a surveillance mechanisms that identifies aberrantly processed mRNA precursors and prevents their flow to the cytoplasm by tethering them near the site of transcription. Termed post-translational modification, this process includes the distinct events of 5′ capping, 3′ polyadenylation, and intron splicing. During processing, nascent mRNA assembles together with RNA binding proteins into ribonucleoprotein particles (mRNPs). Failure to successfully complete any of these maturation steps results in the retention in the nucleus and trigger the mRNA’s degradation. RNA polymerase II is thought to facilitate recruitment of several proteins essential for pre-mRNA processing - the C-terminal domain (CTD) of the largest subunit of RNA Pol II in particular.
Maria Carmo-Fonseca and coworkers in Portugal decided to take a closer look. The CTD, it turns out, is highly conserved, increasing in length and diversifying in structure with the complexity of organisms, presumably via neutral drift. In mammalian cells, the CTD has 52 heptamer (or heptad) repeats, of which follow exactly with the conserved consensus while the remainder display a variety of substitutions. CTD deletion analysis, they write, has shown that heptad repeats a truncated CTD containing 31 repeats (heptads 1-23, 36-38, and 48-52) is sufficient to support transcription, splicing, cleavage, and polyadenylation. Yet, the resulting mRNAs are mostly retained in the vicinity of the gene after transcriptional shutoff, despite also still binding to some of the proteins involved in mRNP export.
So what’s missing? Presumably there’s another protein (or proteins?) necessary for either mRNP maturation or shutting off the retention mechanism, and ~21 of the heptad repeats of RNA pol II are necessary for this to occur. The authors’ attribution of this missing event as a failure to “complete maturation of spliced and 3′ end cleaved/polyadenylated mRNA into export-competent mRNPs” is vague however, and doesn’t quite get to the next question:
How do less complex cells (e.g., yeast, which has 26 heptad repeats in the RNA Pol II CTD) manage to complete maturation and nuclear export of mRNPs, but mammalian cells cannot, even with 31 out of 52? It would seem that the explanation lies in the differences between the two.
- Custodio N, Vivo M, Antoniou M, Carmo-Fonseca M. Splicing- and cleavage-independent requirement of RNA polymerase II CTD for mRNA release from the transcription site.
J. Cell Biol. 2007 179: 199-207. doi: 10.1083/jcb.200612109.
About the Author
Dan Rhoads
Dan is an American working in industry in a small Mediterranean country. He has a BSc in Molecular Biology and a PhD in Cancer Pharmacology and Biochemistry.
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