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Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA

Authors
  • Caval, Vincent1
  • Jiao, Wenjuan1, 2
  • Berry, Noémie1, 3
  • Khalfi, Pierre1, 3
  • Pitré, Emmanuelle1, 3
  • Thiers, Valérie1
  • Vartanian, Jean-Pierre1
  • Wain-Hobson, Simon1
  • Suspène, Rodolphe1
  • 1 Institut Pasteur, Molecular Retrovirology Unit, CNRS UMR 3569, 28 rue du Dr. Roux, Paris cedex 15, 75724, France , Paris cedex 15 (France)
  • 2 Université Paris Diderot, Sorbonne Paris Cité, Paris, France , Paris (France)
  • 3 Sorbonne Université, Complexité du Vivant, ED515, Paris, 75005, France , Paris (France)
Type
Published Article
Journal
BMC Genomics
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Nov 14, 2019
Volume
20
Issue
1
Identifiers
DOI: 10.1186/s12864-019-6216-x
Source
Springer Nature
Keywords
License
Green

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.

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