Thursday, September 18, 2008

Trans-splicing and Chromosomal Translocations

I'm up for the research group journal club tomorrow. Since a couple of the bayblab readers will not be able to make it, I thought I'd pass on what I'll talk about.
A recent publication in Science, demonstrates that an mRNA in a normal endometrial cells encodes the exact same fusion protein that normally occurs as the result of a translocation found in 50% of endometrial cancers. The transcript, as detected by RT-PCR and RNase protection assay is found in abundances that are affected by hormone treatment and hypoxia, suggesting that it has a biological role. In cancer this fusion protein results in resistance to apoptosis and increased proliferation. However, in theses normal cells, there is no DNA encoding for this hybrid mRNA and the authors suggest it is a result of trans-splicing. Trans-splicing of this sort has not been observed in vertabrate cells and even in other organisms it is quite different.
They go to great pains, of course, to demonstrate that it is not an RT-PCR artifact and that there is not a subpopulation of the normal cells that contain the translocation.
The killer is that they do in vitro trans-splicing assays using Rhesus and Human nuclear extracts and indeed find this chimeric mRNA. I'm sure they are looking for other fusion mRNAs using this assay in a high throughput method.
This study raises some intersting question about these oncogenic fusion proteins that are very common in cancer. Particular fusion proteins are repeatedly found in particular cancers. Do they have a function in normal cells? Is it through the mechanism that produces these mRNAs or the mRNAs themselves that cause these cancer associated translocations??
At least check out the figure. Translocation is indicated in the centre of the figure. Two mRNAs combine to create a novel one that has no DNA equivalent.