Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme - Institut Pasteur Access content directly
Journal Articles Nucleic Acids Research Year : 2015

Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme

Abstract

The human APOBEC3A and APOBEC3B genes (A3A and A3B) encode DNA mutator enzymes that deaminate cytidine and 5-methylcytidine residues in single-stranded DNA (ssDNA). They are important sources of mutations in many cancer genomes which show a preponderance of CG->TA transitions. Although both enzymes can hypermutate chromosomal DNA in an experimental setting, only A3A can induce double strand DNA breaks, even though the catalytic domains of A3B and A3A differ by only 9% at the protein level. Accordingly we sought the molecular basis underlying A3B attenuation through the generation of A3A-A3B chimeras and mutants. It transpires that the N-terminal domain facilitates A3B activity while a handful of substitutions in the catalytic C-terminal domain impacting ssDNA binding serve to attenuate A3B compared to A3A. Interestingly, functional attenuation is also observed for the rhesus monkey rhA3B enzyme compared to rhA3A indicating that this genotoxic dichotomy has been selected for and maintained for some 38 million years. Expression of all human ssDNA cytidine deaminase genes is absent in mature sperm indicating they contribute to somatic mutation and cancer but not human diversity.
Fichier principal
Vignette du fichier
gkv935.pdf (651.57 Ko) Télécharger le fichier
Origin : Publication funded by an institution

Dates and versions

pasteur-03520063 , version 1 (10-01-2022)

Licence

Attribution

Identifiers

Cite

Vincent Caval, Mohamed Bouzidi, Rodolphe Suspène, Hélène Laude, Marie-Charlotte Dumargne, et al.. Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme. Nucleic Acids Research, 2015, 43 (19), pp.9340-9349. ⟨10.1093/nar/gkv935⟩. ⟨pasteur-03520063⟩

Collections

PASTEUR
15 View
23 Download

Altmetric

Share

Gmail Facebook X LinkedIn More