Project 170866

It takes 15 000 genes to make a fly and 10 000 more genes to make 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 slightly different way, the protein will play a protective role and will protect against cell death. Cancer cells produce mostly the anti-death version. We wish to understand the molecular events that are responsible for this splicing choice. This knowledge may help designing more efficient treatments and may lead to novel tools to combat cancer. We are proposing to pursue our in-depth characterization of the RNA sequences and proteins involved in the control of Bcl-x splicing. We have already identified several sequence elements and factors that affect splicing decisions on the Bcl-x pre-mRNA. One sequence is involved in the response to a drug that induces the death of cancer cells and shifts splicing to favor the production of the death-inducing version of Bcl-x. Our studies will improve our understanding of alternative splicing, and is designed to discover the switches that control the production of a protein involved in the resistance of cancer cells to chemotherapy.

studying alternative splicing mechanisms in the Bcl-x gene to understand cancer cell resistance to chemotherapy