Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.1 (cytosine deaminase)
747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytosine deaminase APOBEC3G, in the absence of the human immunodeficiency virus type 1 (HIV-1) accessory gene HIV-1 viral infectivity factor (vif), inhibits viral replication by introducing G-->A hypermutation in the newly synthesized HIV-1 DNA negative strand. We tested the hypothesis that genetic variants of APOBEC3G may modify HIV-1 transmission and disease progression. Single nucleotide polymorphisms were identified in the promoter region (three), introns (two), and exons (two). Genotypes were determined for 3,073 study participants enrolled in six HIV-AIDS prospective cohorts. One codon-changing variant, H186R in exon 4, was polymorphic in African Americans (AA) (f = 37%) and rare in European Americans (f < 3%) or Europeans (f = 5%). For AA, the variant allele 186R was strongly associated with decline in CD4 T cells (CD4 slope on square root scale: -1.86, P = 0.009), The 186R allele was also associated with accelerated progression to AIDS-defining conditions in AA. The in vitro antiviral activity of the 186R enzyme was not inferior to that of the common H186 variant. These studies suggest that there may be a modifying role of variants of APOBEC3G on HIV-1 disease progression that warrants further investigation.
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PMID:APOBEC3G genetic variants and their influence on the progression to AIDS. 1545 27

The human proteins APOBEC3F and APOBEC3G restrict retroviral infection by deaminating cytosine residues in the first cDNA strand of a replicating virus. These proteins have two putative deaminase domains, and it is unclear whether one or both catalyze deamination, unlike their homologs, AID and APOBEC1, which are well characterized single domain deaminases. Here, we show that only the C-terminal cytosine deaminase domain of APOBEC3F and -3G governs retroviral hypermutation. A chimeric protein with the N-terminal cytosine deaminase domain from APOBEC3G and the C-terminal cytosine deaminase domain from APOBEC3F elicited a dinucleotide hypermutation preference nearly indistinguishable from that of APOBEC3F. This 5'-TC-->TT mutational specificity was confirmed in a heterologous Escherichia coli-based mutation assay, in which the 5'-CC-->CT dinucleotide hypermutation preference of APOBEC3G also mapped to the C-terminal deaminase domain. An N-terminal APOBEC3G deletion mutant displayed a preference indistinguishable from that of the full-length protein, and replacing the C-terminal deaminase domain of APOBEC3F with AID resulted in an AID-like mutational signature. Together, these data indicate that only the C-terminal domain of APOBEC3F and -3G dictates the retroviral minus strand 5'-TC and 5'-CC dinucleotide hypermutation preferences, respectively, leaving the N-terminal domain to perform other aspects of retroviral restriction.
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PMID:The retroviral hypermutation specificity of APOBEC3F and APOBEC3G is governed by the C-terminal DNA cytosine deaminase domain. 1564 50

Uracil in DNA is a deleterious event that may arise either by cytosine deamination or misincorporation of dUTP. Consequently, cells from all free-living organisms have developed strategies to protect their genome against the presence of uracils, by using uracil DNA glycosylase (UNG) and deoxyuridine triphosphatase (dUTPase) enzymatic activities. In the viral kingdom, some (namely poxviruses and herpesviruses) but not all of the DNA viruses encode their own UNG and dUTPase to control uracilation of their genome. Some retroviruses, which are RNA viruses using DNA as an intermediate of replication, also encode dUTPase. Surprisingly, though most of nonprimate lentiviruses encode dUTPase, primate lentiviruses such as HIV-1, HIV-2 or SIV do not. Because these latter viruses also replicate in nondividing cells where the dUTP/dTTP ratio is high, it is probable that they have found other ways to fight against the emergence of uracilated-viral transcripts. Indeed, recent studies showed that HIV-1 efficiently controls both the cytosine deamination and the dUTP misincorporation. The viral Vif protein acts in preventing the packaging into viral particles of the host-derived cytosine deaminase APOBEC3G enzyme, while the viral integrase domain of the Gag-Pol precursor mediates the packaging of the host-derived uracil DNA glycosylase UNG2 enzyme. In the absence of Vif or UNG2, HIV-1 viral transcripts are heavily charged in uracil bases leading to inactivation of the virus.
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PMID:Uracils as a cellular weapon against viruses and mechanisms of viral escape. 1645 9

We demonstrated previously that the cytosine deaminase APOBEC3G inhibits retrotransposition of two active murine endogenous retroviruses, namely intracisternal A-particles (IAP) and MusD, in an ex vivo assay where retrotransposition was monitored by selection of neo-marked elements. Sequencing of the transposed copies further disclosed extensive editing, resulting in a high load of G-to-A mutations. Here, we asked whether this G-to-A editing was associated with an impact of APOBEC3G on viral cDNA yields. To this end, we used a specially designed quantitative PCR method to selectively measure the copy number of transposed retroelements, in the absence of G418 selection. We show that human APOBEC3G severely reduces the number of MusD and IAP transposed cDNA copies, with no effect on the level of the intermediate RNA transcripts. The magnitude of the decrease closely parallels that observed when transposed copies are assayed by selection of G418-resistant cells. Moreover, sequencing of transposed elements recovered by PCR without prior selection of the cells reveals high-level editing. Using this direct method with a series of cytosine deaminases, we further demonstrate a similar dual effect of African green monkey APOBE3G, human APOBEC3F and murine APOBEC3 on MusD retrotransposition, with a distinct extent and site specificity for each editing activity. Altogether the data demonstrate that cytosine deaminases have a protective effect against endogenous retroviruses both by reducing viral cDNA levels and by introducing mutations in the transposed copies, thus inactivating them for subsequent rounds of retrotransposition. This dual, two-step effect likely participates in the efficient defense of the cell genome against invading endogenous retroelements.
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PMID:Dual inhibitory effects of APOBEC family proteins on retrotransposition of mammalian endogenous retroviruses. 1653 39

The cytosine deaminase APOBEC3G has been identified as a host factor that inhibits HIV-1 replication. We investigated whether genetic variants of APOBEC3G that could potentially affect the protein's expression or function were associated with the risk of infection in 122 Caucasians highly exposed to HIV-1. A novel C40693T variant was significantly associated with an increased risk of infection, suggesting that there might be a role for APOBEC3G in susceptibility to HIV-1 infection that warrants further investigation.
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PMID:APOBEC3G genetic variants and their association with risk of HIV infection in highly exposed Caucasians. 1698 24

The APOBEC3 proteins are unique to mammals. Many inhibit retrovirus infection through a cDNA cytosine deamination mechanism. HIV-1 neutralizes this host defense through Vif, which triggers APOBEC3 ubiquitination and degradation. Here, we report an APOBEC3F-like, double deaminase domain protein from three artiodactyls: cattle, pigs and sheep. Like their human counterparts, APOBEC3F and APOBEC3G, the artiodactyl APOBEC3F proteins are DNA cytosine deaminases that locate predominantly to the cytosol and can inhibit the replication of HIV-1 and MLV. Retrovirus restriction is attributable to deaminase-dependent and -independent mechanisms, as deaminase-defective mutants retain significant anti-retroviral activity. However, unlike human APOBEC3F and APOBEC3G, the artiodactyl APOBEC3F proteins have an active N-terminal DNA cytosine deaminase domain, which elicits a broader dinucleotide deamination preference, and they are resistant to HIV-1 Vif. These data indicate that DNA cytosine deamination; sub-cellular localization and retrovirus restriction activities are conserved in mammals, whereas active site location, local mutational preferences and Vif susceptibility are not. Together, these studies indicate that some properties of the mammal-specific, APOBEC3-dependent retroelement restriction system are necessary and conserved, but others are simultaneously modular and highly adaptable.
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PMID:Evolutionarily conserved and non-conserved retrovirus restriction activities of artiodactyl APOBEC3F proteins. 1703 30

The human APOBEC3G protein is an innate anti-viral factor that can dominantly inhibit the replication of some endogenous and exogenous retroviruses. The prospects of purposefully harnessing such an anti-viral defense are under investigation. Here, long-term co-culture experiments were used to show that porcine endogenous retrovirus (PERV) transmission from pig to human cells is reduced to nearly undetectable levels by expressing human APOBEC3G in virus-producing pig kidney cells. Inhibition occurred by a deamination-independent mechanism, likely after particle production but before the virus could immortalize by integration into human genomic DNA. PERV inhibition did not require the DNA cytosine deaminase activity of APOBEC3G and, correspondingly, APOBEC3G-attributable hypermutations were not detected. In contrast, over-expression of the sole endogenous APOBEC3 protein of pigs failed to interfere significantly with PERV transmission. Together, these data constitute the first proof-of-principle demonstration that APOBEC3 proteins can be used to fortify the innate anti-viral defenses of cells to prevent the zoonotic transmission of an endogenous retrovirus. These studies suggest that human APOBEC3G-transgenic pigs will provide safer, PERV-less xenotransplantation resources and that analogous cross-species APOBEC3-dependent restriction strategies may be useful for thwarting other endogenous as well as exogenous retrovirus infections.
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PMID:The restriction of zoonotic PERV transmission by human APOBEC3G. 1784 22

APOBEC3G is a single-strand DNA cytosine deaminase capable of blocking retrovirus and retrotransposon replication. APOBEC3G has two conserved zinc-coordinating motifs but only one is required for catalysis. Here, deletion analyses revealed that the minimal catalytic domain consists of residues 198-384. Size exclusion assays indicated that this protein is monomeric. Many (31/69) alanine substitution derivatives of APOBEC3G198-384 retained significant to full levels of activity. These data corroborated an APOBEC2-based structural model for the catalytic domain of APOBEC3G indicating that most non-essential residues are solvent accessible and most essential residues cluster within the protein core.
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PMID:Extensive mutagenesis experiments corroborate a structural model for the DNA deaminase domain of APOBEC3G. 1786 48

The human APOBEC3G (apolipoprotein B messenger-RNA-editing enzyme, catalytic polypeptide-like 3G) protein is a single-strand DNA deaminase that inhibits the replication of human immunodeficiency virus-1 (HIV-1), other retroviruses and retrotransposons. APOBEC3G anti-viral activity is circumvented by most retroelements, such as through degradation by HIV-1 Vif. APOBEC3G is a member of a family of polynucleotide cytosine deaminases, several of which also target distinct physiological substrates. For instance, APOBEC1 edits APOB mRNA and AID deaminates antibody gene DNA. Although structures of other family members exist, none of these proteins has elicited polynucleotide cytosine deaminase or anti-viral activity. Here we report a solution structure of the human APOBEC3G catalytic domain. Five alpha-helices, including two that form the zinc-coordinating active site, are arranged over a hydrophobic platform consisting of five beta-strands. NMR DNA titration experiments, computational modelling, phylogenetic conservation and Escherichia coli-based activity assays combine to suggest a DNA-binding model in which a brim of positively charged residues positions the target cytosine for catalysis. The structure of the APOBEC3G catalytic domain will help us to understand functions of other family members and interactions that occur with pathogenic proteins such as HIV-1 Vif.
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PMID:Structure of the DNA deaminase domain of the HIV-1 restriction factor APOBEC3G. 1828 8

The mammalian APOBEC3 proteins are an important component of the cellular innate immune response to retroviral infection. APOBEC3G can extinguish HIV-1 infectivity by its incorporation into virus particles and subsequent cytosine deaminase activity that attacks the nascent viral cDNA during reverse transcription, causing lethal mutagenesis. It has been suggested, but not formally shown, that APOBEC3G can also induce sublethal mutagenesis, which would maintain virus infectivity and contribute to HIV-1 variation. To test this, we developed a novel model system utilizing an HIV-1 vector and a panel of APOBEC3G-expressing cells. We observed proviruses with single APOBEC3G-mediated mutations (in the presence or absence of Vif), occurring at distinct hot spots and which could be rescued and shown to have infectivity. These data indicate that APOBEC3G-dependent restriction of HIV-1 can result in viable viral progeny that harbor sublethal levels of G-to-A mutations. Such mutations have the potential to contribute significantly to HIV-1 evolution, pathogenesis, immune escape, and drug resistance.
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PMID:APOBEC3G contributes to HIV-1 variation through sublethal mutagenesis. 2046 80


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