APOBEC3 proteins (A3A-A3H) catalyse the deamination of cytosine (C) to thymidine (T) on single stranded DNA. This activity, called cytidine deaminase, has initially been described as a mechanism involved in restriction against retroviruses and DNA viruses by massively inducing C->T mutations on viral genome : this phenomenon is called "hypermutations". Nevertheless, this activity is not virus-specific and some A3 can induce mutations on mitochondrial DNA (A3A, C, F, G, H) and nuclear DNA (A3A and A3B). Thus, the impact of those proteins on cancer formation is now established in cancers where mutations mostly show an APOBEC3 signature. In view of those considerations, we decided to study how those enzymes are regulated in the context of a viral cellular stress or an endogenous cellular stress. The first part of our work is focused on A3DE, the only APOBEC3 lacking a cytidine deaminase activity. Interestingly, A3DE is upregulated in cirrhotic livers infected by HBV, HCV or coinfected with HBV & HCV. We show that A3DE inhibits A3F & A3G activity by interacting with those HBV restriction involved A3. Then, we studied the attributes of the genotoxicity potential of A3B. This protein, by his strictly nuclear localization, constitutes the only double domain A3 which is not regulated by A3DE. Unlike A3A, A3B is weakly active on nuclear DNA and does not induce double strand breaks. We determine by directed mutagenesis the clusters of A3B involved in genotoxicity attenuation compared with A3A. We also show that this attenuation is conserved among primates. Finally, we investigated the role and regulation of A3A in the context of DNA catabolism. We proved that mitochondrial cytoplasmic DNA (mtcyDNA) triggers the RIG-I/DNA polymerase III pathway, which induces IFN production leading to A3A expression. So A3A will be involved in mtcyDNA catabolism and contribute to the clearance of this stress signal, but will also induce double strand breaks on nuclear DNA. A3 are major enzymes of the innate immune response and DNA catabolism. We show that A3DE modulates A3F and A3G activity while A3B is attenuated among primates and is less genotoxic than A3A. A3A participates to cytoplasmic DNA catabolism and limits inflammation. Nevertheless, A3A could be dangerous for the genomic integrity and contributes to cancer, especially in cases of chronic inflammation.

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{{Explor lien
   |wiki=    Wicri/Psychologie
   |area=    BernheimV1
   |flux=    Hal
   |étape=   Curation
   |type=    RBID
   |clé=     Hal:tel-01334908
   |texte=   Cellular stress and modulation of APOBEC3 cytidine deaminases activity
}}