RNA Biology linked to DNA damage

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Stéphan Vagner Team Leader Tel:

Understanding regulated gene expression is central to providing insights into biological processes.

Figure 1: Les réseaux de régulation de l’expression des gènes impliquant les facteurs de transcription et les acteurs post-transcriptionnels.
Figure 1: Gene regulatory networks involving regulators of both transcription and post-transcription

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.

We want:

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).

Figure 2: Plan de travail
Figure 2: Working plan

Key publications

Year of publication 2018

Caroline Robert, Stéphan Vagner (2018 Nov 1)

Boosting Immunity by Targeting Post-translational Prenylation of Small GTPases.

Cell : 901-902 : DOI : S0092-8674(18)31385-0
Michaël Cerezo, Ramdane Guemiri, Sabine Druillennec, Isabelle Girault, Hélène Malka-Mahieu, Shensi Shen, Delphine Allard, Sylvain Martineau, Caroline Welsch, Sandrine Agoussi, Charlène Estrada, Julien Adam, Cristina Libenciuc, Emilie Routier, Séverine Roy, Laurent Désaubry, Alexander M Eggermont, Nahum Sonenberg, Jean Yves Scoazec, Alain Eychène, Stéphan Vagner, Caroline Robert (2018 Oct 29)

Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma.

Nature medicine : DOI : 10.1038/s41591-018-0217-1

Year of publication 2017

Michelle Newman, Rym Sfaxi, Abhijit Saha, David Monchaud, Marie-Paule Teulade-Fichou, Stéphan Vagner (2017 Oct 27)

The G-Quadruplex-Specific RNA Helicase DHX36 Regulates p53 Pre-mRNA 3′-End Processing Following UV-Induced DNA Damage.

Journal of Molecular Biology : 429 : 3121-3131 : DOI : 10.1016/j.jmb.2016.11.033

Year of publication 2016

Anne Cammas, Magali Lacroix-Triki, Sandra Pierredon, Morgane Le Bras, Jason S Iacovoni, Marie-Paule Teulade-Fichou, Gilles Favre, Henri Roché, Thomas Filleron, Stefania Millevoi, Stéphan Vagner (2016 Mar 29)

hnRNP A1-mediated translational regulation of the G quadruplex-containing RON receptor tyrosine kinase mRNA linked to tumor progression.

Oncotarget : 7 : 16793-805 : DOI : 10.18632/oncotarget.7589

Year of publication 2014

Lise Boussemart, Hélène Malka-Mahieu, Isabelle Girault, Delphine Allard, Oskar Hemmingsson, Gorana Tomasic, Marina Thomas, Christine Basmadjian, Nigel Ribeiro, Frédéric Thuaud, Christina Mateus, Emilie Routier, Nyam Kamsu-Kom, Sandrine Agoussi, Alexander M Eggermont, Laurent Désaubry, Caroline Robert, Stéphan Vagner (2014 Sep 4)

eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.

Nature : 105-9 : DOI : 10.1038/nature13572
Martin Dutertre, Sarah Lambert, Aura Carreira, Mounira Amor-Guéret, Stéphan Vagner (2014 Mar 1)

DNA damage: RNA-binding proteins protect from near and far.

Trends in biochemical sciences : 141-9 : DOI : 10.1016/j.tibs.2014.01.003
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