Grant: Operating Grant

It takes nearly the same number of genes to make a worm, a fly or a human. The number of genes is therefore not a good predictor of the complexity of an organism. How is the complexity of the human body generated from such a limited set of genes ? A big part of the answer lies in alternative pre-mRNA splicing. Alternative splicing occurs after a gene is transcribed into RNA. Different portions of the pre-mRNAs are combined to produce different types of mRNAs. Thus, through alternative splicing, a single gene can produce many different types of proteins with different activities. The Bcl-x gene is an excellent example of how alternative splicing can make a big difference. When the Bcl-x primary transcript is spliced in one manner, it will produce a protein that can provoke cell death. When it is spliced in a different way, the protein will play a protective role and will protect against cell death. Cancer cells produce mostly the anti-death version of Bcl-x. We wish to understand the molecular events that are implementing these splicing choices. This knowledge may help design more efficient treatments and may lead to novel tools to combat cancer. We are proposing an in-depth characterization of signalling events involved in the control of Bcl-x splicing, particularly in response to drugs that damage DNA and that are used as anti-cancer agents. We also want to determine how this signalling pathway is altered in cancer cells. We plan to expand our findings to other genes involved in cell death and cell division to discover networks of regulation that the cell uses to control the production of functionally relevant splice variants. Our studies will help understand how alternative splicing is controlled in concerted manner to produce proteins that provide cancer cells with an ability to divide and resist death.