Abstract
APOBEC3 are cytidine deaminases that convert cytidine to uridine residues. APOBEC3A and APOBEC3B enzymes able to target genomic DNA are involved in oncogenesis of a sizeable proportion of human cancers. While the APOBEC3 locus is conserved in mammals, it encodes from 1–7 genes. APOBEC3A is conserved in most mammals, although absent in pigs, cats and throughout Rodentia whereas APOBEC3B is restricted to the Primate order. Here we show that the rabbit APOBEC3 locus encodes two genes of which APOBEC3A enzyme is strictly orthologous to human APOBEC3A. The rabbit enzyme is expressed in the nucleus and the cytoplasm, it can deaminate cytidine, 5-methcytidine residues, nuclear DNA and induce double-strand DNA breaks. The rabbit APOBEC3A enzyme is negatively regulated by the rabbit TRIB3 pseudokinase protein which is guardian of genome integrity, just like its human counterpart. This indicates that the APOBEC3A/TRIB3 pair is conserved over approximately 100 million years. The rabbit APOBEC3A gene is widely expressed in rabbit tissues, unlike human APOBEC3A. These data demonstrate that rabbit could be used as a small animal model for studying APOBEC3 driven oncogenesis.
Highlights
Cancer genomics has exploded our understanding of oncogenesis [1, 2]
Through extensive BLAT, BLAST and EST screening, we identified three complete APOBEC3 like Znfinger domains on rabbit chromosome 4
All A3 loci to date are bounded by CBX6 and CBX7 and the rabbit locus was no exception indicating that the entire locus was probably correctly assembled (Figure 1B)
Summary
Cancer genomics has exploded our understanding of oncogenesis [1, 2]. Human cancer genomes harbor thousands to millions of mutations, as well as large numbers of insertions or deletions (indels) and chromosomal rearrangements [3, 4]. Six functional APOBEC3 cytidine deaminases (A3A-A3C and A3F-A3H) are encoded by the human genome and are made up of three related, but phylogenetically distinct zinc-finger domains referred to as Z1, Z2 and Z3 [5]. While the enzymes contain one or a pair of zinc finger domains, only the C-terminal domain is catalytically active. These enzymes convert cytidine residues to uridine in single-stranded DNA (ssDNA), a process referred to as DNA editing. Such substrate specificity distinguishes them from other cytidine deaminases involved in the metabolism of nucleotide precursors [6]
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