|Molecular Retrovirology - CNRS URA 3015|
|HEAD||Prof Simon Wain-Hobson / firstname.lastname@example.org|
|MEMBERS||Marie-Ming Aynaud / Ana de Casas / Dr Anne Gauvrit / Dr,Denise Guetard / Dr Michel Henry / Dr Pierre Langlade / Dr Bianka Mussil / Dr Rodolphe Suspène / Dr Jean-Pierre Vartanian / Leïla Campanaro / Idalina Filipe
The Unit has pursued its work on the genetic editing of viral genomes by the APOBEC and ADAR cytidine and adenosine nucleic acid deaminases. Some of these genes are induced by interferons and constitute powerful viral restriction factors. For hepatitis B virus (HBV) associated cirrhosis the APOBEC3 enzymes are extremely important in the control of HBV replication to the point that we postulate that there may be sanctuaries allowing the virus to persist. Many APOBEC3 genes were strongly up-regulated in virally associated, as opposed to alcoholic cirrhosis, which correlates with the stronger inflammation typical of viral hepatitis. An analysis of animal models for HBV showed that they are restricted by different APOBEC enzymes. In short, in this aspect of their biology, these models do not recapitulate the human infection.
The up-regulation of APOBEC3 genes led us to explore genetic of host cell DNA, that is mitochondrial and nuclear DNA (mt and nuDNA). It transpires that human mtDNA in uncultured samples is undergoing genetic editing. The degree of genetic editing is truly phenomenal; occasionally >90% of cytidine nases are edited. The phenomenon appears to be part of a novel DNA catabolic pathway involving APOBEC3 deamination and uracil DNA-glucosylase / abasic endonuclease enzymes. Further work showed that one APOBEC3 enzyme in particular could edit nuDNA. This raises the spectre that they could be involved in oncogenesis. Our findings fit in well with two findings from the exploding field of cancer genomics, that is that diseased cancer genomes harbour tens of thousands of mutations of which the cytidine to thymidine transition is the most fréquent.
These findings have pushed the unit resolutely into the field of cancer research which fits in well with our work on the immunological potential of telomerase to control cancers. In transgenic mice we have shown that telomerase, which is strongly up-regulated in most cancers, is capable of inducing very strong cell mediated responses that lead to the protection against challenge by an aggressive melanoma. This led to the creation in 2010 of Invectys, a Pasteur based biotech company exploiting an exclusive Pasteur patent, dedicated to therapeutic vaccination against human cancers.
Keywords: APOBEC3 , CANCER, CYTIDINE DEAMINASE, GENETIC EDITING
Vartanian JP, D Guétard, M. Henry and S Wain-Hobson. 2008. Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and pre-cancerous lesions Science 320,230-233
Suspène R, M Renard, M Henry, D Puyraimond-Zemmour, A Billecocq, M Bouloy,F Tangy, JP Vartanian and S Wain-Hobson. 2008. Inverting the natural hydrogen bonding rule to selectively amplify GC-rich ADAR edited RNAs. Nucleic Acids Research 36, e72
Petit V, D Guétard, A Keriel, M Sitbon, S Wain-Hobson and JP Vartanian. 2009. Murine APOBEC1 deaminates Fr-MLV RNA and DNA in vitroand in vivo. Journal of Molecular Biology 385, 65-78
Adotevi O, K Mollier, C Neuveut, M Dosset, P Ravel, W-H Fridman, E Tartour, P Charneau, S Wain-Hobson and P Langlade-Demoyen. 2010. Targeting human telomerase reverse transcriptase (hTERT) with recombinant lentivector is highly effective to stimulate antitumor CD8 T-cell immunity in vivo
Blood 115, 2025-3032. Vartanian JP, M Henry, A Marchio, R Suspène, MM Aynaud, D Guétard, M Cervantes-Gonzalez, C Battiston, V Mazzaferro, P Pineau, A Dejean and S Wain-Hobson. 2010. Massive APOBEC3 editing of hepatitis B viral DNA in cirrhosis. PLoS Pathogens 6, e1000928
Activity Reports 2010 - Institut Pasteur
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