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Esnault, C. et al. APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses. Nature 433, 430-433

Unité des Rétrovirus Endogènes et Eléments Retroïdes des Eucaryotes Supérieurs, UMR8122 CNRS, Institut Gustave Roussy, Villejuif 94805, France.
Nature (Impact Factor: 41.46). 02/2005; 433(7024):430-3. DOI: 10.1038/nature03238
Source: PubMed

ABSTRACT

Endogenous retroviruses are multicopy retroelements accounting for nearly 10% of murine or human genomes. These retroelements spread into our ancestral genome millions of years ago and have acted as a driving force for genome evolution. Endogenous retroviruses may also be deleterious for their host, and have been implicated in cancers and autoimmune diseases. Most retroelements have lost replication competence because of the accumulation of inactivating mutations, but several, including some murine intracisternal A-particle (IAP) and MusD sequences, are still mobile. These elements encode a reverse transcriptase activity and move by retrotransposition, an intracellular copy-and-paste process involving an RNA intermediate. The host has developed mechanisms to silence their expression, mainly cosuppression and gene methylation. Here we identify another level of antiviral control, mediated by APOBEC3G, a member of the cytidine deaminase family that was previously shown to block HIV replication. We show that APOBEC3G markedly inhibits retrotransposition of IAP and MusD elements, and induces G-to-A hypermutations in their DNA copies. APOBEC3G, by editing viral genetic material, provides an ancestral wide cellular defence against endogenous and exogenous invaders.

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    • "We also identified an UE mouse intracisternal A particle (IAP) retroelement, bearing 189 edited sites. This was anticipated, as IAP elements have been shown to be edited by murine APOBEC3 (Esnault et al. 2005; Carmi et al. 2011) (fig. 4). "
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    ABSTRACT: LTR retrotransposons are widespread in vertebrates and their dynamism facilitates genome evolution. However, these endogenous retroviruses (ERVs) must be restricted to maintain genomic stability. The APOBECs, a protein family that can edit C-to-U in DNA, do so by interfering with reverse transcription and hypermutating retrotransposon DNA. In some cases, a retrotransposon may integrate into the genome despite being hypermutated. Such an event introduces a unique sequence into the genome, increasing retrotransposon diversity and the probability of developing new function at the locus of insertion. The prevalence of this phenomenon and its effects on vertebrate genomes are still unclear. In this study, we screened ERV sequences in the genomes of 123 diverse species and identified hundreds of thousands of edited sites in multiple vertebrate lineages, including placental mammals, marsupials and birds. Numerous edited ERVs carry high mutation loads, some with >350 edited sites, profoundly damaging their ORFs. For many of the species studied, this is the first evidence that APOBECs are active players in their innate immune system. Unexpectedly, some birds and especially zebra finch and medium-ground finch (one of Darwin's finches), are exceptionally enriched in DNA editing. We demonstrate that edited retrotransposons may be preferentially retained in active genomic regions, as reflected from their enrichment in genes, exons, promoters and transcription start sites, thereby raising the probability of their exaptation for novel function. In conclusion, DNA editing of retrotransposons by APOBECs has a substantial role in vertebrate innate immunity and may boost genome evolution.
    Preview · Article · Nov 2015 · Molecular Biology and Evolution
    • "The intrinsic restriction factor APOBEC3G is a cytosine deaminase that inhibits the retrotransposition of endogenous retroviruses (Esnault et al., 2005, 2006). It is hypothesized that APOBEC3G is most active in germ cells and during early embryogenesis, when HERVs are also thought to be active due to hypomethylation (Esnault et al., 2005). Furthermore, there is evidence of past activity by a cytosine deaminase, resulting in the hypermutation of HERVs (Lee et al., 2008). "
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    ABSTRACT: The human genome comprises 8 % endogenous retroviruses (ERVs), the majority of which are defective due to deleterious mutations. Nonetheless, transcripts of ERVs are found in most tissues, and these transcripts could either be reverse transcribed to generate ssDNA or expressed to generate proteins. Thus, the expression of ERVs could produce nucleic acids or proteins with viral signatures, much like the pathogen-associated molecular patterns of exogenous viruses, which would enable them to be detected by the innate immune system. The activation of some pattern recognition receptors (PRRs) in response to ERVs has been described in mice and in the context of human autoimmune diseases. Here, we review the evidence for detection of ERVs by PRRs and the resultant activation of innate immune signalling. This is an emerging area of research within the field of innate antiviral immunity, showing how ERVs could initiate immune signalling pathways and might have implications for numerous inflammatory diseases. © 2015 The Authors.
    No preview · Article · Dec 2014 · Journal of General Virology
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    • "Endogenous retroelements include retrotransposons and endogenous retroviruses. Exogenous retroelements include retroviruses of several genera (Lentivirus, Alpha-, Beta-, Gamma-, Delta-retrovirus and foamy viruses) (Chiu and Green, 2008; Mangeat et al., 2003; Zhang et al., 2003; Turelli et al., 2004; Wiegand and Cullen, 2007; Chen et al., 2006; Okeoma et al., 2007; Esnault et al., 2005; Kinomoto et al., 2007). The APOBEC3 proteins appear to exert their inhibitory activity through a deaminase-dependent mechanisms, which deaminates cytosine to uracils and through an incompletely understood deaminase-independent mechanism (Narvaiza et al., 2009). "
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    ABSTRACT: The Apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (APOBEC3) genes are able to inhibit the replication of a wide range of exogenous retroviruses, as well as endogenous retroviruses and retrotransposons. Three APOBEC3 genes, named APOBEC3Z1, APOBEC3Z2 and APOBEC3Z3, have been described in sheep. In this work the three genes have been screened in order to identify polymorphisms. No polymorphism was detected for the A3Z2 and A3Z3 genes but 16 SNPs and a 3-bp deletion were found in the A3Z1 gene. A thermoestability prediction analysis was applied to the detected amino acidic SNPs by three different programs. This analysis revealed a number of polymorphisms that could affect the protein stability. The SNPs of the 3'UTR were tested to detect alterations on the predicted microRNA target sites. Two new microRNA target sites were discovered for one of the alleles. Two SNPs were selected for association studies in relation with the retroviral disease Visna/Maedi in Latxa and Assaf sheep breeds. Although association analyses resulted unconclusive, probably due to the unsuitability of the SNP allele frequency distribution of the selected polymorphisms in the analyzed breeds, these genes remain good candidates for association studies. Copyright © 2014 Elsevier B.V. All rights reserved.
    Full-text · Article · Nov 2014 · Veterinary Immunology and Immunopathology
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