Powerful mutators lurking in the genome

Petit, Vincent; Vartanian, Jean‐Pierre; Wain‐Hobson, Simon

doi:10.1098/rstb.2008.0272

Cited by 17 publications

(13 citation statements)

References 102 publications

(131 reference statements)

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“…It is known that APOBEC3 family members are potentially powerful mutators [31-33]. We reasoned that interaction of DND1 with APOBEC3 in germ cells may be one mechanism to keep the latent deleterious activity of APOBEC3 in check.…”

Section: Resultsmentioning

confidence: 99%

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APOBEC3 inhibits DEAD-END function to regulate microRNA activity

et al. 2013

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The RNA binding protein DEAD-END (DND1) is one of the few proteins known to regulate microRNA (miRNA) activity at the level of miRNA-mRNA interaction. DND1 blocks miRNA interaction with the 3′-untranslated region (3′-UTR) of specific mRNAs and restores protein expression. Previously, we showed that the DNA cytosine deaminase, APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide like 3), interacts with DND1. APOBEC3 has been primarily studied for its role in restricting and inactivating retroviruses and retroelements. In this report, we examine the significance of DND1-APOBEC3 interaction. We found that while human DND1 inhibits miRNA-mediated inhibition of P27, human APOBEC3G is able to counteract this repression and restore miRNA activity. APOBEC3G, by itself, does not affect the 3′-UTR of P27. We found that APOBEC3G also blocks DND1 function to restore miR-372 and miR-206 inhibition through the 3′-UTRs of LATS2 and CX43, respectively. In corollary experiments, we tested whether DND1 affects the viral restriction function or mutator activity of APOBEC3. We found that DND1 does not affect APOBEC3 inhibition of infectivity of exogenous retrovirus HIV (ΔVif) or retrotransposition of MusD. In addition, examination of Ter/Ter;Apobec3−/− mice, lead us to conclude that DND1 does not regulate the mutator activity of APOBEC3 in germ cells. In summary, our results show that APOBEC3 is able to modulate DND1 function to regulate miRNA mediated translational regulation in cells but DND1 does not affect known APOBEC3 function.

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Section: Resultsmentioning

confidence: 99%

“…Thus APOBEC3 family members are potentially powerful mutators [33] and very likely cells possess mechanisms to keep the latent deleterious activity of APOBEC3 in check. One way that cells protect their genomes from APOBEC3 is that mouse APOBEC3 and most human APOBEC3 proteins are localized to the cytoplasm [14,29,34].…”

Section: Introductionmentioning

confidence: 99%

APOBEC3 inhibits DEAD-END function to regulate microRNA activity

et al. 2013

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“…Although it remains unclear which A3 protein causes TC mutation of HPV in vivo, A3A has been a candidate based on its tissue distribution, along with two other APOBEC proteins, APOBEC3C and APOBEC3H (reviewed in Ref. 67). The finding that endogenous A3A is highly enzymatically active in at least one primary cell type (monocytes/ MDMs), reported here and by Stenglein et al (57), provides yet another reason why A3A is an attractive candidate for causing HPV mutations in vivo.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Thielen

McNevin

McElrath

et al. 2010

Journal of Biological Chemistry

105

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In HIV-1-infected individuals, G-to-A hypermutation is found in HIV-1 DNA isolated from peripheral blood mononuclear cells (PBMCs). These mutations are thought to result from editing by one or more host enzymes in the APOBEC3 (A3) family of cytidine deaminases, which act on CC (APOBEC3G) and TC (other A3 proteins) dinucleotide motifs in DNA (edited cytidine underlined). Although many A3 proteins display high levels of deaminase activity in model systems, only low levels of A3 deaminase activity have been found in primary cells examined to date. In contrast, here we report high levels of deaminase activity at TC motifs when whole PBMCs or isolated primary monocyte-derived cells were treated with interferon-␣ (IFN␣) or IFN␣-inducing toll-like receptor ligands. Induction of TC-specific deaminase activity required new transcription and translation and correlated with the appearance of two APOBEC3A (A3A) isoforms. Knockdown of A3A in monocytes with siRNA abolished TC-specific deaminase activity, confirming that A3A isoforms are responsible for all TC-specific deaminase activity observed. Both A3A isoforms appear to be enzymatically active; moreover, our mutational studies raise the possibility that the smaller isoform results from internal translational initiation. In contrast to the high levels of TC-specific activity observed in IFN␣-treated monocytes, CC-specific activity remained low in PBMCs, suggesting that A3G deaminase activity is relatively inhibited, unlike that of A3A. Together, these findings suggest that deaminase activity of A3A isoforms in monocytes and macrophages may play an important role in host defense against viruses. A33 proteins are cytidine deaminases that are capable of inhibiting replication of retroviruses, DNA viruses, and retroelements (reviewed in Refs. 1-3). The seven A3 proteins in the human genome share a strong preference for deaminating cytidines that are in a CC or TC context in single-stranded DNA (edited cytidine underlined). Although APOBEC3G (A3G), the best understood A3 protein, acts preferentially on CC motifs, the six other human A3 proteins display varying degrees of preference for TC motifs (4 -13). Because other cytidine deaminases, such as activation-induced deaminase and APOBEC1, either display a strong preference for editing deoxycytidines in other dinucleotide contexts or act on TC motifs in RNA (4), mutations that arise in a CC or TC context in DNA constitute signatures of editing by A3 proteins.Much headway has been made in understanding how A3 proteins act on HIV-1 DNA, in part through transfection of A3 plasmids into human epithelium-derived cell lines, such as 293T or HeLa cells, which lack significant endogenous expression of most A3 proteins. From such studies, A3G and APOBEC3F (A3F) are known to be packaged into virus particles when the HIV-1 Vif protein is not expressed and to cause a substantial reduction in virus infectivity (5, 12, 14 -16). Reduced virus infectivity results in part from non-enzymatic inhibition of reverse transcription by A3G and A3F (17-2...

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“…In recent years, it was shown that active LTR (long terminal repeat) retrotransposons, which are endogenous retroviruses, can also be edited [14][15][16][17][18][19][20][21] . However, the impact of DNA editing on genome variability has not been explored to date 22 .…”

mentioning

confidence: 99%

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

2011

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Retrotransposons had an important role in genome evolution, including the formation of new genes and promoters and the rewiring of gene networks. However, it is unclear how such a repertoire of functions emerged from a relatively limited number of source sequences. Here we show that DnA editing, an antiviral mechanism, accelerated the evolution of mammalian genomes by large-scale modification of their retrotransposon sequences. We find numerous pairs of retrotransposons containing long clusters of G-to-A mutations that cannot be attributed to random mutagenesis. These clusters, which we find across different mammalian genomes and retrotransposon families, are the hallmark of APoBEC3 activity, a potent antiretroviral protein family with cytidine deamination function. As DnA editing simultaneously generates a large number of mutations, each affected element begins its evolutionary trajectory from a unique starting point, thereby increasing the probability of developing a novel function. our findings thus suggest a potential mechanism for retrotransposon domestication.

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Powerful mutators lurking in the genome

Cited by 17 publications

References 102 publications

APOBEC3 inhibits DEAD-END function to regulate microRNA activity

APOBEC3 inhibits DEAD-END function to regulate microRNA activity

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

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