Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage

Rodolphe Suspene (1) , Bianka Mussil (2, 3) , Hélène Laude (2) , Vincent Caval (2) , Noémie Berry (2) , Mohamed Bouzidi (2) , Valerie Thiers (2) , Simon Wain-Hobson (1) , Jean Pierre Vartanian (1)

1 Rétrovirologie Moléculaire
2 Rétrovirologie Moléculaire
3 GPC - DPZ - German Primate Center - Deutsches Primatenzentrum -- Leibniz Insitute for Primate Research -- [Göttingen, Allemagne]

Foreign and self-cytoplasmic DNA are recognized by numerous DNA sensor molecules leading to the production of type I interferons. Such DNA ago-nists should be degraded otherwise cells would be chronically stressed. Most human APOBEC3 cytidine deaminases can initiate catabolism of cytoplasmic mitochondrial DNA. Using the human myeloid cell line THP-1 with an interferon inducible APOBEC3A gene, we show that cytoplasmic DNA triggers inter-feron and production through the RNA poly-merase III transcription/RIG-I pathway leading to massive upregulation of APOBEC3A. By catalyzing C→U editing in single stranded DNA fragments, the enzyme prevents them from re-annealing so attenuating the danger signal. The price to pay is chromo-somal DNA damage in the form of CG→TA mutations and double stranded DNA breaks which, in the context of chronic inflammation, could drive cells down the path toward cancer.

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology; Life Sciences [q-bio]; Immunology; Innate immunity

Rodolphe Suspene, Bianka Mussil, Hélène Laude, Vincent Caval, Noémie Berry, et al.. Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage. Nucleic Acids Research, 2017, 45, pp.gkx001. ⟨10.1093/nar/gkx001⟩. ⟨pasteur-02065335⟩