Hypermutation by intersegmental transfer of APOBEC3G cytidine deaminase

Roni Nowarski, Elena Britan-Rosich, Tamar Shiloach, Moshe Kotler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Deamination of cytidine residues in single-stranded DNA (ssDNA) is an important mechanism by which apolipoprotein B mRNA-editing, catalytic polypeptide-like (APOBEC) enzymes restrict endogenous and exogenous viruses. The dynamic process underlying APOBEC-induced hypermutation is not fully understood. Here we show that enzymatically active APOBEC3G can be detected in wild-type Vif(+) HIV-1 virions, albeit at low levels. In vitro studies showed that single enzyme-DNA encounters result in distributive deamination of adjacent cytidines. Nonlinear translocation of APOBEC3G, however, directed scattered deamination of numerous targets along the DNA. Increased ssDNA concentrations abolished enzyme processivity in the case of short, but not long, DNA substrates, emphasizing the key role of rapid intersegmental transfer in targeting the deaminase. Our data support a model by which APOBEC3G intersegmental transfer via monomeric binding to two ssDNA segments results in dispersed hypermutation of viral genomes.

Original languageAmerican English
Pages (from-to)1059-1066
Number of pages8
JournalNature Structural and Molecular Biology
Volume15
Issue number10
DOIs
StatePublished - Oct 2008

Bibliographical note

Funding Information:
This work was carried out in the Krueger Laboratory with the support of N. and L. Glick, and P. and M. Weiss. We thank K. Strebel (US National Institutes of Health (NIH), Bethesda, Maryland, USA) for providing pcDNA-APOBEC3G. We thank E. Pikarsky, R. Harris and H. Matsuo for constructive and helpful discussion, and S. Amir for editing this manuscript. Anti-APOBEC3G-C-terminal antibody was obtained from J. Lingappa through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. This work was supported in part by the Israel Ministry of Industry Trade & Labor via the Nofar program, the Israel Ministry of Health and the United States-Israel Binational Science Foundation (BSF).

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