Nucleophosmin and Polyadenylation
The processing of pre-mRNAs to generate mature mRNAs is a complex event that is closely coordinated with transcription. Three interdependent steps are required for most transcripts, namely capping, splicing and 3’ end processing. Due to the complexity of signals involved, errors inevitably occur so the cell has developed surveillance mechanisms to weed out and destroy aberrant mRNAs that have failed to process correctly at one or more steps. For example, during splicing, successful intron removal results in deposition of a protein complex termed the Exon Junction Complex (EJC) just upstream of each intron. This EJC influences efficiency of export and translation of the resulting mRNA and, if it is inappropriately positioned, can induce rapid mRNA decay.
Our laboratory discovered that polyadenylation results in the deposition of a protein called nucleophosmin (NPM) on mRNAs just upstream of the poly(A) site (Figure 1;Palaniswamy et al (2006)).
Nucleophosmin is over-expressed in cancer cells and has been implicated in many cellular processes. Our recent results have shown that knockdown of nucleophosmin results in accumulation of mRNAs with extended poly(A) tails. Moreover, poly(A) RNA fails to exit efficiently to the cytoplasm in these knockdown cells. NPM appears to interact directly with polyadenylation factors to control poly(A) tail length (Sagawa et al 2011). We are currently investigating the mechanism of NPM mediated poly(A) tail length control.