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Elephant APOBEC3A cytidine deaminase induces massive double-stranded DNA breaks and apoptosis

Abstract : The incidence of developing cancer should increase with the body mass, yet is not the case, a conundrum referred to as Peto's paradox. Elephants have a lower incidence of cancer suggesting that these animals have probably evolved different ways to protect themselves against the disease. The paradox is worth revisiting with the realization that most mammals encode an endogenous APOBEC3 cytidine deaminase capable of mutating single stranded DNA. Indeed, the mutagenic activity of some APOBEC3 enzymes has been shown to introduce somatic mutations into genomic DNA. These enzymes are now recognized as causal agent responsible for the accumulation of CG-> TA transitions and DNA breaks leading to chromosomal rearrangements in human cancer genomes. Here, we identified an elephant A3Z1 gene, related to human APOBEC3A and showed that it could efficiently deaminate cytidine, 5-methylcytidine and produce DNA breaks leading to massive apoptosis, similar to other mammalian APOBEC3A enzymes where body mass varies by up to four orders of magnitude. Consequently, it could be considered that eAZ1 might contribute to cancer in elephants in a manner similar to their proposed role in humans. If so, eAZ1 might be particularly well regulated to counter Peto's paradox. The APOBEC3 (A3) locus is bounded by two conserved genes, chromobox 6 and 7 (CBX6 and CBX7) in most pla-cental mammals and encodes a family of cytidine deaminases capable of converting cytidine residues to uridine in single strand DNA (ssDNA). The mutagenic activity of these enzymes is involved with the restriction of retro-viruses and DNA viruses, as well as endogenous retroelements and retrotransposons through hypermutation of viral DNA in a process called editing 1. The A3 repertoire is extremely variable among mammals, the locus being shaped through extensive gene duplications and functionalization in the context of a virus-host arms race. A3 enzymes are made up of three related, but distinct zinc-finger domains referred to as Z1, Z2 and Z3 2-4 presumably already present in the genome of the ancestor of placental mammals 5. The last few years has seen the identification of two human endogenous A3 cytidine deaminases, APOBEC3A (A3A) and APOBEC3B (A3B) capable of introducing multiple mutations in chromosomal DNA 6-9. These findings are grounded by the analysis of many cancer genomes, revealing far more mutations and rearrangements than hitherto imagined, where CG-> TA transitions appears to be the dominant mutations 10-13. Human A3A is composed of a single Z1 domain, while A3B is composed of a double Z2Z1 domain, although only the C terminal Z1 domain being catalytically functional 6. A3A and A3B enzymes are both localized in the nucleus and can edit cytidine residues to uridine in ssDNA during transcription and replication, following DNA repair, and leave TpC to TpT signature mutations that show up in cancer genomes 6,8,9. Both enzymes can mutate 5-methylcytidine (5MeC) to thymidine leaving another distinct signature in cancer genomes 6,14-16. Although A3A and A3B are accepted as intrinsic mutators of cellular chromosomal DNA, analyzed in several cancer types 8,11,17 , debate still persists regarding the contribution of each enzyme in the accumulation of mutations paving the way for oncogenesis. While, it has been described that A3A and A3B could be enzymat-ically active in different cancers 18 , A3A is the more active of the two enzymes and as a consequence, only A3A can produce double stranded breaks (DSBs), at least in an experimental setting 6,7,19. Editing frequencies of >0.5 can be found which is why the phenomenon is referred to as hyperediting or hypermutation 9. Accumulation of substitutions localized in the A3B C-terminal domain attenuated the activity of the enzyme compared to A3A 6 .
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Xiongxiong Li, Vincent Caval, Simon Wain-Hobson, Jean-Pierre Vartanian. Elephant APOBEC3A cytidine deaminase induces massive double-stranded DNA breaks and apoptosis. Scientific Reports, Nature Publishing Group, 2019, 9 (1), pp.728. ⟨10.1038/s41598-018-37305-z⟩. ⟨pasteur-02065280⟩



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