We are developing new therapeutic approaches to correct nonsense mutations that represent 5 to 40% of the mutations affecting the tumor suppressor genes and responsible for also about 10% of any genetic diseases.
> ENGINEERS / TECHNICIANS
Fabrice LEJEUNE – Researcher (CRCN) INSERM
Research: Correction of nonsense mutations and study of the mechanisms leading to the recognition of premature termination codons.
Keywords: nonsense mutations, nonsense-mediated mRNA decay (NMD, readthrough, targeted therapeutic approaches, screening, genetic diseases.
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Catherine AMPEN-GUFFROY – Engineer (IE) CNRS
Molecular and Cellular Biology, Biochemistry, Bioinformatics, Animal experimentation, Health and safety (radiation protection advisor).
Correction of nonsense mutations in cancers and other genetic diseases
Colocalization in cytoplasmic foci in HeLa cells of UPF1 (green) and DCP1a (red) upon colchicine treatment
Nonsense mutations change a codon into a premature termination codon. The consequence of the presence of a premature termination codon is the absence of expression of the gene due to the activation of a quality control mechanism named nonsense-mediated mRNA decay (NMD). Approximatively 10% of patients with a genetic disease are due to a premature termination codon. Genetic diseases include rare diseases such as cystic fibrosis, Duchenne muscular dystrophy, Rett syndrome, etc… and also frequent pathologies like metabolic or neurologic disorders and cancers.
In the lab, we search for molecules capable of rescuing the functional expression of genes carrying a nonsense mutation. For that we developed screening systems to identify molecules that inhibit NMD and/or activate PTC-readthrough (Gonzales et al., Orphanet Journal of Rare diseases 2012, Benhabiles et al., Plos One 2017, Trzaska et al., Nature Commun 2020). Screen selected molecules are then tested on cell and mouse models carrying a nonsense mutation in TP53, PTEN, CFTR or dystrophin gene in order to characterize the molecules and understand how they work. We aim to develop new therapeutic approaches for genetic diseases caused by nonsense mutations and to improve our knowledge on the mechanisms recognizing premature termination codons and their regulation. Past studies from our lab demonstrated that NMD is inhibited during apoptosis due to caspase cleavages of two main NMD factors named UPF1 and UPF2 (Jia et al., Cell Death and Diff, 2015).
We also found that cytoskeleton disruptors are strong NMD inhibitors. The study of these molecules lead us to identify and characterize new cytoplasmic foci in which PTC readthrough occurs and that we named readthrough bodies (Jia et al., J Cell Science, 2017).
Trzaska C, Amand S, Bailly C, Leroy C, Marchand V, Duvernois-Berthet E, Saliou JM, Benhabiles H, Werkmeister E, Chassat T, Guilbert R, Hannebique D, Mouray A, Neu-Yilik G, Copin MC, Moreau PA, Prévotat A, Reix P, Hubert D, Gérardin M, Adriaenssens E, Hentze M, Kulozik A, Westhof E, Tulasne D, Motorin Y, Rebuffat S and Lejeune F. 2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations. Nat Commun. 2020 In Press. IF 11.878
Bokhari A, Jonchere V, Lagrange A, Bertrand R, Svrcek M, Marisa L, Buhard O, Greene M, Demidova A, Jia J, Adriaenssens E, Chassat T, Biard DS, Flejou JF, Lejeune F, Duval A, Collura A. Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability. Oncogenesis. 2018 Sep 19;7(9):70; IF 5.995
Lejeune F. Nonsense-mediated mRNA decay at the crossroads of many cellular pathways. BMB Rep. 2017 Apr;50(4):175-185. Review IF 3.089