APOBEC3G hypermutates genomic DNA and inhibits Ty1 retrotransposition in yeast
TLDR
It is demonstrated that APOBEC3G is capable of deaminating genomic cytosines in Saccharomyces cerevisiae and postulate that the APOBec3-dependent innate cellular defense constitutes a tightly regulated arm of a conserved mobile nucleic acid restriction mechanism that is poised to limit internal as well as external assaults.Abstract:
Human cells harbor a variety of factors that function to block the proliferation of foreign nucleic acid. The APOBEC3G enzyme inhibits the replication of retroviruses by deaminating nascent retroviral cDNA cytosines to uracils, lesions that can result in lethal levels of hypermutation. Here, we demonstrate that APOBEC3G is capable of deaminating genomic cytosines in Saccharomyces cerevisiae. APOBEC3G expression caused a 20-fold increase in frequency of mutation to canavanine-resistance, which was further elevated in a uracil DNA glycosylase-deficient background. All APOBEC3G-induced base substitution mutations mapped to the nuclear CAN1 gene and were exclusively C/G → T/A transition mutations within a 5′-CC consensus. The APOBEC3G preferred sites were found on both strands of the DNA duplex, but were otherwise located in hotspots nearly identical to those found previously in retroviral cDNA. This unique genetic system further enabled us to show that expression of APOBEC3G or its homolog APOBEC3F was able to inhibit the mobility of the retrotransposon Ty1 by a mechanism that involves the deamination of cDNA cytosines. Thus, these data expand the range of likely APOBEC3 targets to include nuclear DNA and endogenous retroelements, which have pathological and physiological implications, respectively. We postulate that the APOBEC3-dependent innate cellular defense constitutes a tightly regulated arm of a conserved mobile nucleic acid restriction mechanism that is poised to limit internal as well as external assaults.read more
Citations
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An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers
Steven A. Roberts,Michael S. Lawrence,Leszek J. Klimczak,Sara A. Grimm,David C. Fargo,Petar Stojanov,Adam Kiezun,Gregory V. Kryukov,Gregory V. Kryukov,Scott L. Carter,Gordon Saksena,Shawn F. Harris,Ruchir R. Shah,Michael A. Resnick,Gad Getz,Gad Getz,Dmitry A. Gordenin +16 more
TL;DR: It is shown that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates withAPOBEC mRNA levels, and that ubiquitous APOBec-mediated Mutagenesis are carcinogenic.
Journal ArticleDOI
The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements.
Ya-Lin Chiu,Warner C. Greene +1 more
TL;DR: Current understanding of the mechanism of action of the APOBEC3 family of enzymes, their intriguing regulation within cells, the impact of these enzymes on viral evolution and disease progression, and their roles in controlling not only the replication of exogenous retroviruses but also the retrotransposition of endogenous retroelements are summarized.
Journal ArticleDOI
APOBECs and virus restriction
TL;DR: The sensitivity of viruses that lack counterdefense measures highlights the need to develop APOBEC-enabling small molecules as a new class of anti-viral drugs.
Journal ArticleDOI
APOBEC3 Proteins Inhibit Human LINE-1 Retrotransposition
Heide Muckenfuss,Matthias Hamdorf,Ulrike Held,Mario Perkovic,Johannes Löwer,Klaus Cichutek,Egbert Flory,Gerald G. Schumann,Carsten Münk +8 more
TL;DR: Evidence is presented for a role of host-encoded APOBEC3 proteins in the regulation of L1 retrotransposition and sequence analyses did not reveal an enhanced rate of G-to-A transitions, suggesting a mechanism independent of DNA deamination.
Journal ArticleDOI
HIV-1 Vif, APOBEC, and intrinsic immunity.
Ritu Goila-Gaur,Klaus Strebel +1 more
TL;DR: The goal of this review is to recapitulate current knowledge of the functional interaction of HIV-1 and its Vif protein with the APOBEC3 subfamily of proteins and to summarize the present understanding of the mechanism of APOBec3-dependent retrovirus restriction.
References
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Journal ArticleDOI
Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein
TL;DR: A unique cellular gene, CEM15, is described, whose transient or stable expression in cells that do not normally express Cem15 recreates this phenotype, but whose antiviral action is overcome by the presence of Vif.
Journal ArticleDOI
Studies on the transformation of intact yeast cells by the LiAc/SS‐DNA/PEG procedure
TL;DR: The LiAc/SS‐DNA/PEG method was shown to be more effective than other treatments known to make cells transformable and caused tighter binding of 32P‐labelled plasmid DNA than did double‐stranded (DS) carrier.
Journal ArticleDOI
Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts
TL;DR: It is demonstrated that APOBEC3G exerts its antiviral effect during reverse transcription to trigger G-to-Ahypermutation in the nascent retroviral DNA, suggesting that hypermutation by editing is a general innate defence mechanism against this important group of pathogens.
PatentDOI
DNA deamination mediates innate immunity to (retro)viral infection
Michael H. Malim,Ann M. Sheehy,Reuben S. Harris,Kate Bishop,Michael S. Neuberger,Nathan Gaddis,James H. M. Simon +6 more
TL;DR: Evidence is provided that CEM15/APOBEC3G is a DNA deaminase that is incorporated into virions during viral production and subsequently triggers massive deamination of deoxycytidine to deoxyuridine within the retroviral minus (first)-strand cDNA, thus providing a probable trigger for viral destruction.
Journal ArticleDOI
Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex
TL;DR: In this paper, the ability of Vif to suppress antiviral activity of APOBEC3G was specifically dependent on Cul5-SCF function, allowing Vif-specific SCF to interact with APOBec3G and induce its ubiquitination and degradation.