The Deciphering & drugging DNA Repair (DDR) lab aims at deciphering how human cells respond to DNA damage to identify and validate new druggable complexes for cancer treatment. Our landmark discoveries include alternative End-Joining (2004), mechanisms antagonizing Ku association to some DNA ends (2016, 2020), a new function for BRCA1 at centromeres (2014, 2021), the characterization of Ku interactions with DNA repair factors (2018, 2023) and the discovery of the mechanism of action of several bioactive small molecules (2017, 2021, 2022).
DNA repair controls the outcome of several anticancer therapies. As such there is a huge interest for novel small molecules modulating DNA repair. In the DDR lab, we decipher how cells respond to DNA damage, more specifically to the most harmful type, DNA Double-Strand Breaks (DSBs). We use the resulting knowledge to design and perform targeted and phenotypical based screens to identify new modulators of specific aspects of the DNA damage response. To achieve our goals, we rely on high- and super-resolution imaging, molecular and cell biology, genomics, small molecules screening, chemical probes and on multiple collaborations with structural biologists and chemists. We recently implemented in the lab several complementary approaches to decipher how biologically active small molecules act (Bombarde et al. Mol Cancer Ther 2017; Bossaert, Pipier et al. 2021; Demange, Joly, Marcoux et al. eLife 2022).
The interplay between DNA repair mechanisms
Two principal DSB repair mechanisms co-exist in human cells: Non- Homologous End Joining (NHEJ) and Homologous Recombination (HR). Using a new method for imaging NHEJ proteins, we recently discovered the main mechanism antagonizing NHEJ proteins association to special DSBs, thereby allowing HR to proceed. We established that these mechanisms are druggable and that their inhibition triggers toxic DNA repair events in response to some anticancer agents (Britton et al. 2013 J Cell Biol; Chanut, Britton et al. 2016 Nat Commun; Britton, Chanut et al. 2020 Nucleic Acids Res).
How DNA repair proteins associate on damaged chromatin
We recently characterized how the repair factors APLF and XLF associate with the NHEJ core protein Ku at DNA damage, thereby characterizing two new interaction interfaces at the functional and structural levels (Nemoz, Ropars, Frit et al. 2018 Nat Struct Mol Biol; Seif-El-Dahan, Kefala-Stavridi, Frit, Hardwick et al. 2023). We also investigate how the genomic context, such as heterochromatin and transcription, affect DNA repair and genome stability. Using laser micro-irradiation and live imaging, we discovered a novel mechanism promoting the exclusion of a large number of RNA-binding proteins from DNA damage sites, thereby preventing the local accumulation of R-loops (Britton, Dernoncourt et al. Nucleic Acids Res 2014).
How stabilizing specific DNA structures triggers DNA damage
Small molecules stabilizing secondary DNA structures, such as G-quadruplexes (G4) ligands, trigger DNA damage (Zell et al. 2020 RSC Chem Biol). Through an unbiased genomic approach, we recently discovered that DNA topoisomerase 2 alpha is responsible for the production of DSB by several G4 ligands (Bossaert, Pipier et al. 2021 eLife), including CX-5461 a molecule undergoing clinical trials in oncology. We also contributed to develop novel ligands of another secondary structure, the Three-way Junction, and established that they also trigger DNA damage by a mechanism that we are currently investigating (Duskova 2019 J Med Chem; Duskova et al. 2020 J Am Chem Soc; Zell et al. Nucleic Acids Res 2021).
Nadia Barboule (CNRS)
Sébastien Britton (CNRS)
Patrick Calsou (Inserm)
Philippe Frit (CNRS)
Dennis Gomez (CNRS)
Florence Larminat (CNRS)
Marie-Jeanne Pillaire (Inserm)
Antonio Peixoto (CNRS)
Carine Racca (CNRS)
Maria Fidelia Susanto
Demange, Joly, Marcoux, et al (2022) SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species. eLife
Bossaert, Pipier, et al (2021) Transcription-associated topoisomerase 2alpha (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands. eLife
Racca et al (2021) BRCA1 prevents R-loop-associated centromeric instability. Cell death & disease
Britton, Chanut et al (2020) ATM antagonizes NHEJ proteins assembly and DNA-ends synapsis at single-ended DNA double strand breaks. Nucleic Acids Res
Zell et al (2021) Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells. Nucleic Acids Res
Nemoz, Ropars, Frit et al (2018) XLF and APLF bind Ku80 at two remote sites to ensure DNA repair by non-homologous end joining. Nat Struct Mol Biol
High-resolution imaging of DNA Double-Strand Breaks (DSBs) in human cells treated with ionizing radiations in presence of a DDR inhibitor. Red: DSBs visualized with gammaH2AX; Green: Actin cytoskeleton; Blue: DNA.
© Sébastien Britton.
- Françoise Benoit-Vical (LCC, UPR8241)
- Remi Chauvin and Valérie Maraval (LCC, UPR8241)
- Mamadou Daffé/Hedia Marrakchi (IPBS)
- G. Favre/Olivier Sordet (CRCT, UMR1037)
- Amine Khamlichi (IPBS)
- Yves Génisson (SPCMIB, UMR5068)
- Gaëlle Legube (CBI-LBCMCP)
- Lionel Mourey (IPBS)
- Stefania Millevoi (CRCT, UMR1037)
- Céline Noirot (Genotoul Bioinfo)
- Olivier Saurel/Andrew Atkinson (IPBS) and PICT platform
- Odile Schiltz (IPBS)
- Genotoul GeT-PlaGe
- Yves-Jean Bignon and Nancy Uhrhammer (Centre Jean Perrin, Clermont-Ferrand)
- Isabelle Callebaut (IMPMC, Paris)
- Jean-Baptiste Charbonnier (I2BC, Saclay)
- Patrick Dallemagne (CERMN, Caen)
- Eric Defrancq (I2BM, Grenoble)
- Marc Delarue (Institut Pasteur, Paris)
- Daniele Fachinetti (Institut Curie, Paris)
- Claire Francastel (Paris Epigenetics, Paris)
- Anton Granzham (Institut Curie, Paris)
- Valérie Lamour (IGBMC, Strasbourg)
- Jean-Louis Mergny (IECB, Bordeaux)
- Mauro Modesti (CRCM, Marseille)
- David Monchaud (ICMUB, Dijon)
- Jean-François Riou (MNHN, Paris)
- Jean-Pierre de Villartay (Institut Imagine, Paris)
- Steve Jackson (The Gurdon Institute, Cambridge, UK)
- Murray Junop (McMaster University, Canada)
- Susan Lees-Miller (University of Calgary, Canada)
- Michael Lieber (USC, Los Angeles, USA)
- Jo Loparo (Harvard Medical School, Boston, USA)
- Sankar Mitra (Houston Methodist Research Institute, USA)
- Eric van Dick (Luxembourg Institute of Health, Luxembourg)
- 2022 ANR “inJUNCTION”, collaboration between S.Britton, D. Monchaud, A. Granzhan, N. Chéron and L. Trantirek.
- 2022 ANR “MAG4”, to D.Gomez, collaboration with F. Benoit-Vical and V. Gervais.
- 2022 INCA PLBIO collaboration between M.-J. Pillaire, S. Manenti and C. Joffre.
- 2022 Roche ROADS program to A. Peixoto.
- 2022 Cancéropôle Grand-Sud-Ouest – Soutien à l’Emergence. Projet “CRIM”.
- 2022 Ligue Régionale contre le Cancer to S. Britton, collaboration with Y. Génisson.
- 2021 Prématuration Région Occitanie “Prostacure” to S. Britton, collaboration with Y. Génisson and R. Chauvin/V. Maraval.
- 2021 ANR “iCARE”, collaboration between D.Gomez, E. Defrancq, M. Delarue, A. Granzhan, J.-L. Mergny, J.-F. Riou.
- 2020 ANR “BreakDance”, collaboration between P. Calsou, J.-B. Charbonnier, M. Delarue, M. Modesti.
- 2020 ANR “MELICENDRe”, collaboration between F. Larminat, C. Francastel and D. Fachinetti.
- 2019 Pre-Maturation grant from SATT-TTT to S. Britton, collaboration with Y. Génisson & R. Chauvin.
- 2019 Plan Cancer Aviesan “DDRi” to S. Britton, collaboration with P. Dallemagne, CERMN, Caen.
- 2019 Plan Cancer Aviesan “ANASTOMOSIS” to P.Calsou, collaboration with D. Monchaud, ICMUB, Dijon.
- 2019 Cancéropôle Grand-Sud-Ouest – Soutien à l’Emergence. Projet “KILR”.
- 2019 Cancéropôle Grand-Sud-Ouest – Soutien à l’Emergence. Projet “CX-Break”.
- 2018-2020 Labellisation Ligue Nationale Contre le Cancer “Cassures double-brin de l’ADN : mécanismes de réparation et connexions thérapeutiques en oncologie”.
- 2018 Programme Prématuration Région Occitanie “OPTIBREAK”, collaboration with Pascal demange, Lionel Mourey, Yves Génisson.
- 2017 ANR “NHEJ LIG4″, collaboration with M. Modesti and J.-B. Charbonnier”
- 2017 Fondation ARC. “Development of new anticancer agents”.
- 2017 ANR JCJC to S. Britton. “Drugging DNA repair complexes”.
- 2016 IDEX “Fishing out the intracellular target of novel antitumor pharmacophores bio-inspired from marine sponge” collaboration between S.Britton, Y. Génisson and R. Chauvin.
- 2016 ANR “G4-TopIPro” collaboration between D. Gomez, E. Defrancq and J.-F. Riou.
- 2016 Cancéropôle Grand Sud-Ouest – Soutien à l’Emergence (Cibles pharmacologiques de la Jaspine B) to S. Britton & P. Calsou.
- 2016 Cancéropôle Grand Sud-Ouest – Soutien à l’Emergence (G4POPSTAR, collaboration with G. Pratviel and S. Millevoi).
- 2016 Electricité de France – Conseil de Radioprotection.
- 2015 Electricité de France – Conseil de Radioprotection.