Understanding regulated gene expression is central to providing insights into biological processes.
Whereas much effort has been placed on deciphering transcriptional regulation through interactions of hundreds of transcriptional factors with functional DNA elements, little is known about an equally sizeable number of molecules (called mRNA binding proteins (mRBP) and non-coding RNAs (ncRNAs) including microRNAs (miRNAs)) that directly and specifically interact with cis-acting elements of messenger RNAs (mRNAs) and control the metabolism of transcribed mRNAs, a process called post-transcriptional gene expression (Fig. 1).
Recent studies have also emphasized how every step of mRNA metabolism (splicing, polyadenylation, translation, stability) is prone not only to dynamic regulation but also to various alterations in human diseases including cancer. Post-transcriptional control of gene expression is therefore more pervasive than previously thought.
More specifically, the general importance of post-transcriptional regulatory circuits as part of the DNA damage response (DDR) is becoming increasingly recognized. Therefore, uncovering the mechanisms whereby the post-transcriptional machinery refines the proteomic complexity required for the DDR and permits cells to respond to genotoxic stresses in the context of global inhibition of gene expression represents a major breakthrough. This constitutes the main objective of our work that we will follow in three main directions.
Axis 1- to examine whether the coordinated regulation of post-transcriptional steps of gene expression, from splicing/polyadenylation of pre-mRNAs to translation of mRNAs, contributes to the response/resistance to chemotherapies (PI: Martin Dutertre),
Axis 2- to understand the mechanisms by which RNA binding proteins (RBPs) accomplish DNA damage-induced changes in post-transcriptional steps of gene expression (PI: Stéphan Vagner),
Axis 3- to evaluate the possibility to target post-transcriptional regulators to sensitize tumor cells to anti-cancer targeted therapies and radiotherapy (PI: Stéphan Vagner).
To tackle these issues, we use a combination of biochemical, cellular biology and functional genomic approaches that allow us to characterize the mechanisms controlled by RBPs and to identify, in a high throughput manner, alterations in RNA-protein interactions (Fig. 2).