Abstract
BackgroundAPOBEC1 (A1) enzymes are cytidine deaminases involved in RNA editing. In addition to this activity, a few A1 enzymes have been shown to be active on single stranded DNA. As two human ssDNA cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B) and related enzymes across the spectrum of placental mammals have been shown to introduce somatic mutations into nuclear DNA of cancer genomes, we explored the mutagenic threat of A1 cytidine deaminases to chromosomal DNA.ResultsMolecular cloning and expression of various A1 enzymes reveal that the cow, pig, dog, rabbit and mouse A1 have an intracellular ssDNA substrate specificity. However, among all the enzymes studied, mouse A1 appears to be singular, being able to introduce somatic mutations into nuclear DNA with a clear 5’TpC editing context, and to deaminate 5-methylcytidine substituted DNA which are characteristic features of the cancer related mammalian A3A and A3B enzymes. However, mouse A1 activity fails to elicit formation of double stranded DNA breaks, suggesting that mouse A1 possess an attenuated nuclear DNA mutator phenotype reminiscent of human A3B.ConclusionsAt an experimental level mouse APOBEC1 is remarkable among 12 mammalian A1 enzymes in that it represents a source of somatic mutations in mouse genome, potentially fueling oncogenesis. While the order Rodentia is bereft of A3A and A3B like enzymes it seems that APOBEC1 may well substitute for it, albeit remaining much less active. This modifies the paradigm that APOBEC3 and AID enzymes are the sole endogenous mutator enzymes giving rise to off-target editing of mammalian genomes.
Highlights
APOBEC1 (A1) enzymes are cytidine deaminases involved in ribonucleic acid (RNA) editing
Synthesis and expression of mammalian APOBEC1 sequences Mammalian A1 complementary deoxyribonucleic acid (DNA) (cDNA) sequences from several species were retrieved by data mining and synthesized (Fig. 1a, Additional file 1: Table S1)
A1 cDNAs were cloned in pcDNA3.1 V5-tag encoding expression vector, as well as in a dual promoter vector simultaneously encoding Bacillus subtilis phage uracil-DNA glycosylase inhibitor (UGI) gene under a phosphoglycerate kinase (PGK) promoter
Summary
APOBEC1 (A1) enzymes are cytidine deaminases involved in RNA editing. In addition to this activity, a few A1 enzymes have been shown to be active on single stranded DNA. The APOBEC3 (A3) locus, delineated by two conserved genes, chromobox 6 and 7 (CBX6 and CBX7), is present in all placental mammals and encodes a diverse repertoire of single stranded DNA cytidine deaminases [22,23,24]. These enzymes are involved in the restriction of many retroviruses [25,26,27,28], DNA viruses [29,30,31], as. These observations are supported by experimental data [37, 38] and a posteriori analyses of many cancer genomes, displaying far more mutations and rearrangements than hitherto imagined, where the CG ➔ TA transitions appear to be the dominant mutations [39,40,41]
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