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Mutator Effects and Mutation Signatures of Editing Deaminases Produced in Bacteria and Yeast

A. G. Lada1, C. Frahm Krick1, S. G. Kozmin2, V. I. Mayorov3, T. S. Karpova4, I. B. Rogozin5,6, and Y. I. Pavlov1*

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA; E-mail: ypavlov@unmc.edu

2Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA

3Mercer University School of Medicine, Macon, GA 31207, USA

4National Cancer Institute, Center for Cancer Research Core Imaging Facility, Laboratory of Receptor Biology and Gene Expression, Bethesda, MD, 20892, USA

5National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA

6Institute of Cytology and Genetics, 630090 Novosibirsk, Russia

* To whom correspondence should be addressed.

Received September 10, 2010
Enzymatic deamination of bases in DNA or RNA leads to an alteration of flow of genetic information. Adenosine deaminases edit RNA (ADARs, TADs). Specialized cytidine deaminases are involved in RNA/DNA editing in lipid metabolism (APOBEC1) and in innate (APOBEC3 family) and humoral (AID) immunity. APOBEC2 is required for proper muscle development and, along with AID, was implicated in demethylation of DNA. The functions of APOBEC4, APOBEC5, and other deaminases recently discovered by bioinformatics approaches are unknown. What is the basis for the diverse biological functions of enzymes with similar enzyme structure and the same principal enzymatic reaction? AID, APOBEC1, lamprey CDA1, and APOBEC3G enzymes cause uracil DNA glycosylase-dependent induction of mutations when overproduced ectopically in bacteria or yeast. APOBEC2, on the contrary, is nonmutagenic. We studied the effects of the expression of various deaminases in yeast and bacteria. The mutagenic specificities of four deaminases, hAID, rAPOBEC1, hAPOBEC3G, and lamprey CDA1, are strikingly different. This suggests the existence of an intrinsic component of deaminase targeting. The expression of yeast CDD1 and TAD2/TAD3, human APOBEC4, Xanthomonas oryzae APOBEC5, and deaminase encoded by Micromonas sp. gene MICPUN_56782 was nonmutagenic. A lack of a mutagenic effect for Cdd1 is expected because the enzyme functions in the salvage of pyrimidine nucleotides, and it is evolutionarily distant from RNA/DNA editing enzymes. The reason for inactivity of deaminases grouped with APOBEC2 is not obvious from their structures. This can not be explained by protein insolubility and peculiarities of cellular distribution and requires further investigation.
KEY WORDS: editing deaminases, mutagenesis, immunity, DNA repair

DOI: 10.1134/S0006297911010135