The RNA splicing response to DNA damage
Description: It takes nearly the same number of genes to make a worm or a human. A big part of what makes biological complexity lies not in the number of genes but rather in the alternative splicing of transcripts when a gene is transcribed into RNA. Alternative splicing is the act of combining different portions of a pre-mRNA to produce different types of mRNAs. Through alternative splicing, a single gene can produce many types of proteins with different activities. The Bcl-x gene is one example of how this can make a big difference. When the Bcl-x transcript is spliced one way, it produces a protein that provokes cell death. When it is spliced in a different way, as in cancer cells, it protects against cell death. The goal of many anti-cancer agents is to create sufficient DNA damage for a signal to be sent to switch Bcl-x production in favor of the pro-death version. For maximal efficacy, this response needs to be coordinated with the production of splicing variants from many other genes important for repairing DNA damage and cell growth. Our objective is to understand the regulatory events that underlie such splicing choices to help design more efficient treatments and novel tools to combat cancer. We propose to determine to what extent proteins that regulate Bcl-x splicing coordinate the splicing of other genes critical for the fate of the cell, particularly after DNA damage. Essentially, our hypothesis is that DNA damaging agents disturb alternative splicing by altering the activity of splicing regulators. The identification of these regulators can lead to new ways to kill cancer cells. We have demonstrated the amazing potential of this approach by identifying a group of small molecules that kill colorectal cancer cells efficiently and with specificity by interfering with the activity of an important regulator of the splicing response to DNA damage. We propose to characterize their mechanisms of action in a human model of colorectal cancer.
Amount: CA$823,900
Funding type: research
Funder scheme: Project Grant
Start date: 2019-10-01
End date: 2024-09-30
Investigator: Benoit Chabot
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 9
Funder award ID: 165966_1
OpenAlex ID: G1769749518