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.
"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). "
"The human Apobec3 locus encodes seven homologous genes expanded in tandem on chromosome 22  . Human APOBEC3 proteins catalyze deamination of cytidines in single-stranded DNA (ssDNA), providing innate protection against retroviral replication and retrotransposition     , as well as against hepatitis B and several DNA viruses    . "
[Show abstract][Hide abstract] ABSTRACT: Deamination of cytidine residues in viral DNA (vDNA) is a major mechanism by which APOBEC3G (A3G) inhibits vif-deficient HIV-1 replication. dC to dU transition following RNase-H activity leads to viral cDNA degradation, production of non-functional proteins, formation of undesired stop codons and decreased viral protein synthesis. Here we demonstrate that A3G provides an additional layer of defence against HIV-1 infection dependent on inhibition of proviral transcription. HIV-1 transcription elongation is regulated by the trans-activation response (TAR) element, a short stem-loop RNA structure required for elongation factors binding. Vif-deficient HIV-1-infected cells accumulate short viral transcripts and produce lower amounts of full-length HIV-1 transcripts due to A3G deamination of the TAR apical loop cytidine, highlighting the requirement for TAR loop integrity in HIV-1 transcription. Finally, we show that free ssDNA termini are not essential for A3G activity and a gap of CCC motif blocked with juxtaposed DNA or RNA on either or 3'+5' ends is sufficient for A3G deamination, identifying A3G as an efficient mutator, and that deamination of (-)SSDNA results in an early block of HIV-1 transcription.
"hA3G is known to be an intrinsic retroviral restriction factor that inhibits Vif-defective human immunodeficiency virus type 1 (HIV-1) infection by being incorporated into viral particles and mediating extensive deamination of the nascent minus-strand viral DNA during reverse transcription, which results in G-to-A hypermutation [20-23]. This antiretroviral restriction extends to not only exogenous retroviruses, such as simian immunodeficiency virus [24-27], primate foamy virus [28,29], human T-cell leukemia virus type I , murine leukemia virus [21,26,31], mouse mammary tumor virus , and equine infectious anemia virus  , but also endogenous retroelements, such as the MusD and intracisternal A-particle LTR murine retrotransposons and, as described below, human Alu and L1 retrotransposons ([33-40]; see also review in ref.). hA3G also restricts infection by hepatitis B virus, which replicates its DNA genome by reverse transcription of an RNA intermediate [42,43]. "
[Show abstract][Hide abstract] ABSTRACT: Alu and LINE-1 (L1), which constitute ~11% and ~17% of the human genome, respectively, are transposable non-LTR retroelements. They transpose not only in germ cells but also in somatic cells, occasionally causing cancer. We have previously demonstrated that antiretroviral restriction factors, human APOBEC3 (hA3) proteins (A-H), differentially inhibit L1 retrotransposition. In this present study, we found that hA3 members also restrict Alu retrotransposition at differential levels that correlate with those observed previously for L1 inhibition. Through deletion analyses based on the best-characterized hA3 member human APOBEC3G (hA3G), its N-terminal 30 amino acids were required for its inhibitory activity against Alu retrotransposition. The inhibitory effect of hA3G on Alu retrotransposition was associated with its oligomerization that was affected by the deletion of its N-terminal 30 amino acids. Through structural modeling, the amino acids 24 to 28 of hA3G were predicted to be located at the interface of the dimer. The mutation of these residues resulted in abrogated hA3G oligomerization, and consistently abolished the inhibitory activity of hA3G against Alu retrotransposition. Importantly, the anti-L1 activity of hA3G was also associated with hA3G oligomerization. These results suggest that the inhibitory activities of hA3G against Alu and L1 retrotransposition might involve a common mechanism.
PLoS ONE 12/2013; 8(12):e84228. DOI:10.1371/journal.pone.0084228 · 3.23 Impact Factor
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