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Michael S Neuberger - One of the best experts on this subject based on the ideXlab platform.
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dna deaminases induce break associated mutation showers with implication of APOBEC3b and 3a in breast cancer kataegis
eLife, 2013Co-Authors: Benjamin Taylor, Cristina Rada, Serena Nikzainal, Lucy Stebbings, Keiran Raine, Peter J Campbell, Michael R Stratton, Michael S NeubergerAbstract:Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis. DOI:http://dx.doi.org/10.7554/eLife.00534.001.
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dna deamination in immunity aid in the context of its APOBEC relatives
Advances in Immunology, 2007Co-Authors: Silvestro G Conticello, Marcandre Langlois, Zizhen Yang, Michael S NeubergerAbstract:Abstract The activation‐induced cytidine deaminase (AID)/apolipoprotein B RNA‐editing catalytic component (APOBEC) family is a vertebrate‐restricted subgrouping of a superfamily of zinc (Zn)‐dependent deaminases that has members distributed throughout the biological world. AID and APOBEC2 are the oldest family members with APOBEC1 and the APOBEC3s being later arrivals restricted to placental mammals. Many AID/APOBEC family members exhibit cytidine deaminase activity on polynucleotides, although in different physiological contexts. Here, we examine the AID/APOBEC proteins in the context of the entire Zn‐dependent deaminase superfamily. On the basis of secondary structure predictions, we propose that the cytosine and tRNA deaminases are likely to provide better structural paradigms for the AID/APOBEC family than do the cytidine deaminases, to which they have conventionally been compared. These comparisons yield predictions concerning likely polynucleotide‐interacting residues in AID/APOBEC3s, predictions that are supported by mutagenesis studies. We also focus on a specific comparison between AID and the APOBEC3s. Both are DNA deaminases that function in immunity and are responsible for the hypermutation of their target substrates. AID functions in the adaptive immune system to diversify antibodies with targeted DNA deamination being central to this function. APOBEC3s function as part of an innate pathway of immunity to retroviruses with targeted DNA deamination being central to their activity in retroviral hypermutation. However, the mechanism by which the APOBEC3s fulfill their function of retroviral restriction remains unresolved.
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evolution of the aid APOBEC family of polynucleotide deoxy cytidine deaminases
Molecular Biology and Evolution, 2005Co-Authors: Silvestro G Conticello, Svend K Petersenmahrt, Cornelia Thomas, Michael S NeubergerAbstract:The AID/APOBEC family (comprising AID, APOBEC1, APOBEC2, and APOBEC3 subgroups) contains members that can deaminate cytidine in RNA and/or DNA and exhibit diverse physiological functions (AID and APOBEC3 deaminating DNA to trigger pathways in adaptive and innate immunity; APOBEC1 mediating apolipoprotein B RNA editing). The founder member APOBEC1, which has been used as a paradigm, is an RNA-editing enzyme with proposed antecedents in yeast. Here, we have undertaken phylogenetic analysis to glean insight into the primary physiological function of the AID/APOBEC family. We find that although the family forms part of a larger superfamily of deaminases distributed throughout the biological world, the AID/APOBEC family itself is restricted to vertebrates with homologs of AID (a DNA deaminase that triggers antibody gene diversification) and of APOBEC2 (unknown function) identifiable in sequence databases from bony fish, birds, amphibians, and mammals. The cloning of an AID homolog from dogfish reveals that AID extends at least as far back as cartilaginous fish. Like mammalian AID, the pufferfish AID homolog can trigger deoxycytidine deamination in DNA but, consistent with its cold-blooded origin, is thermolabile. The fine specificity of its mutator activity and the biased codon usage in pufferfish IgV genes appear broadly similar to that of their mammalian counterparts, consistent with a coevolution of the antibody mutator and its substrate for the optimal targeting of somatic mutation during antibody maturation. By contrast, APOBEC1 and APOBEC3 are later evolutionary arrivals with orthologs not found in pufferfish (although synteny with mammals is maintained in respect of the flanking loci). We conclude that AID and APOBEC2 are likely to be the ancestral members of the AID/APOBEC family (going back to the beginning of vertebrate speciation) with both APOBEC1 and APOBEC3 being mammal-specific derivatives of AID and a complex set of domain shuffling underpinning the expansion and evolution of the primate APOBEC3s.
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comparison of the differential context dependence of dna deamination by APOBEC enzymes correlation with mutation spectra in vivo
Journal of Molecular Biology, 2004Co-Authors: Rupert Beale, Svend K Petersenmahrt, Ian N Watt, Cristina Rada, Michael S NeubergerAbstract:To investigate the extent to which in vivo mutation spectra might reflect the intrinsic specificities of active mutators, genetic and biochemical assays were used to analyse the DNA target specificities of cytidine deaminases of the APOBEC family. The results reveal the critical importance of nucleotides immediately 5′ of the targeted C for the specificity of all three enzymes studied (AID, APOBEC1 and APOBEC3G). At position −1, APOBEC1 showed a marked preference for dT, AID for dA/dG and APOBEC3G a strong preference for dC. Furthermore, AID and APOBEC3G showed distinct dependence on the nucleotide at position −2 with dA/dT being favoured by AID and dC by APOBEC3G. Most if not all activity of the recombinant deaminases on free dC could be attributed to low-level contamination by host enzymes. The target preference of APOBEC3G supports it being a major but possibly not sole contributor to HIV hypermutation without making it a dominant contribution to general HIV sequence variation. The specificity of AID as deduced from the genetic assay (which relies on inactivation of sacB of Bacillus subtilis) agrees well with that deduced by Pham et al. using an in vitro assay although we postulate that major intrinsic mutational hotspots in immunoglobulin V genes in vivo might reflect favoured sites of AID action being generated by proximal DNA targets located on opposite DNA strands. The target specificity of AID also accords with the spectrum of mutations observed in B lymphoma-associated oncogenes. The possibility of deaminase involvement in non-lymphoid human tumours is hinted at by tissue-specific differences in the spectra of dC transitions in tumour-suppressor genes. Thus, the patterns of hypermutation in antibodies and retroviruses owe much to the intrinsic sequence preferences of the AID/APOBEC family of DNA deaminases: analogous biases might also contribute to the spectra of cancer-associated mutation.
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in vitro deamination of cytosine to uracil in single stranded dna by apolipoprotein b editing complex catalytic subunit 1 APOBEC1
Journal of Biological Chemistry, 2003Co-Authors: Svend K Petersenmahrt, Michael S NeubergerAbstract:Abstract Apolipoprotein B-editing complex catalytic subunit 1 (APOBEC1) is the catalytic component of an RNA-editing complex that deaminates C6666 → U in apolipoprotein B RNA in gastrointestinal tissue, thereby generating a premature stop codon. Whereas RNA is the physiological substrate of APOBEC1, recent experiments have strongly indicated that, when expressed in bacteria, APOBEC1 and some of its homologues can deaminate cytosine in DNA. Indeed, genetic evidence demonstrates that the physiological function of activation-induced deaminase, a B lymphocyte-specific APOBEC1 homologue, is to perform targeted deamination of cytosine within the immunoglobulin locus, thereby triggering antibody gene diversification. However, biochemical evidence of in vitro DNA deamination by members of the APOBEC family is still needed. Here, we show that deamination of cytosine to uracil in DNA can be achieved in vitro using partially purified APOBEC1 from extracts of transformed Escherichia coli. Thus, APOBEC1 can deaminate cytosine in both RNA and DNA. Strikingly, its activity on DNA is specific for single-stranded DNA and exhibits dependence on local sequence context.
Silvestro G Conticello - One of the best experts on this subject based on the ideXlab platform.
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evidence for host dependent rna editing in the transcriptome of sars cov 2
Science Advances, 2020Co-Authors: Salvatore Di Giorgio, Giorgio Mattiuz, Filippo Martignano, Maria Torcia, Silvestro G ConticelloAbstract:The COVID-19 outbreak has become a global health risk, and understanding the response of the host to the SARS-CoV-2 virus will help to combat the disease. RNA editing by host deaminases is an innate restriction process to counter virus infection, but it is not yet known whether this process operates against coronaviruses. Here, we analyze RNA sequences from bronchoalveolar lavage fluids obtained from coronavirus-infected patients. We identify nucleotide changes that may be signatures of RNA editing: adenosine-to-inosine changes from ADAR deaminases and cytosine-to-uracil changes from APOBEC deaminases. Mutational analysis of genomes from different strains of Coronaviridae from human hosts reveals mutational patterns consistent with those observed in the transcriptomic data. However, the reduced ADAR signature in these data raises the possibility that ADARs might be more effective than APOBECs in restricting viral propagation. Our results thus suggest that both APOBECs and ADARs are involved in coronavirus genome editing, a process that may shape the fate of both virus and patient.
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evidence for rna editing in the transcriptome of 2019 novel coronavirus
bioRxiv, 2020Co-Authors: Salvatore Di Giorgio, Giorgio Mattiuz, Filippo Martignano, Maria Torcia, Silvestro G ConticelloAbstract:Abstract The 2019-nCoV outbreak has become a global health risk. Editing by host deaminases is an innate restriction process to counter viruses, and it is not yet known whether it operates against coronaviruses. Here we analyze RNA sequences from bronchoalveolar lavage fluids derived from two Wuhan patients. We identify nucleotide changes that may be signatures of RNA editing: Adenosine-to-Inosine changes from ADAR deaminases and Cytosine-to-Uracil changes from APOBEC ones. A mutational analysis of genomes from different strains of human-hosted Coronaviridae reveals patterns similar to the RNA editing pattern observed in the 2019-nCoV transcriptomes. Our results suggest that both APOBECs and ADARs are involved in Coronavirus genome editing, a process that may shape the fate of both virus and patient.
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A fluorescent reporter for quantification and enrichment of DNA editing by APOBEC-Cas9 or cleavage by Cas9 in living cells.
Nucleic acids research, 2018Co-Authors: Amber St. Martin, Silvestro G Conticello, Artur A Serebrenik, Nadine M. Shaban, Francesco Donati, Uday Munagala, Reuben S. HarrisAbstract:Base editing is an exciting new genome engineering technology. C-to-T mutations in genomic DNA have been achieved using ribonucleoprotein complexes comprised of rat APOBEC1 single-stranded DNA deaminase, Cas9 nickase (Cas9n), uracil DNA glycosylase inhibitor (UGI), and guide (g)RNA. Here, we report the first real-time reporter system for quantification of APOBEC-mediated base editing activity in living mammalian cells. The reporter expresses eGFP constitutively as a marker for transfection or transduction, and editing restores functionality of an upstream mCherry cassette through the simultaneous processing of two gRNA binding regions that each contain an APOBEC-preferred 5'TCA target site. Using this system as both an episomal and a chromosomal editing reporter, we show that human APOBEC3A-Cas9n-UGI and APOBEC3B-Cas9n-UGI base editing complexes are more efficient than the original rat APOBEC1-Cas9n-UGI construct. We also demonstrate coincident enrichment of editing events at a heterologous chromosomal locus in reporter-edited, mCherry-positive cells. The mCherry reporter also quantifies the double-stranded DNA cleavage activity of Cas9, and may therefore be adaptable for use with many different CRISPR systems. The combination of a rapid, fluorescence-based editing reporter system and more efficient, structurally defined DNA editing enzymes broadens the versatility of the rapidly expanding toolbox of genome editing and engineering technologies.
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the rna editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas
Genome Biology, 2014Co-Authors: Giulia Saraconi, Francesco Severi, Cesare Sala, Giorgio Mattiuz, Silvestro G ConticelloAbstract:Background: The AID/APOBECs are deaminases that act on cytosines in a diverse set of pathways and some of them have been linked to the onset of genetic alterations in cancer. Among them, APOBEC1 is the only family member to physiologically target RNA, as the catalytic subunit in the Apolipoprotein B mRNA editing complex. APOBEC1 has been linked to cancer development in mice but its oncogenic mechanisms are not yet well understood. Results: We analyze whether expression of APOBEC1 induces a mutator phenotype in vertebrate cells, likely through direct targeting of genomic DNA. We show its ability to increase the inactivation of a stably inserted reporter gene in a chicken cell line that lacks any other AID/APOBEC proteins, and to increase the number of imatinib-resistant clones in a human cellular model for chronic myeloid leukemia through induction of mutations in the BCR-ABL1 fusion gene. Moreover, we find the presence of an AID/APOBEC mutational signature in esophageal adenocarcinomas, a type of tumor where APOBEC1 is expressed, that mimics the one preferred by APOBEC1 in vitro. Conclusions: Our findings suggest that the ability of APOBEC1 to trigger genetic alterations represents a major layer in its oncogenic potential. Such APOBEC1-induced mutator phenotypes could play a role in the onset of esophageal adenocarcinomas. APOBEC1 could be involved in cancer promotion at the very early stages of carcinogenesis, as it is highly expressed in Barrett's esophagus, a condition often associated with esophageal adenocarcinoma.
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the aid APOBEC family of nucleic acid mutators
Genome Biology, 2008Co-Authors: Silvestro G ConticelloAbstract:The AID/APOBECs, a group of cytidine deaminases, represent a somewhat unusual protein family that can insert mutations in DNA and RNA as a result of their ability to deaminate cytidine to uridine. The ancestral AID/APOBECs originated from a branch of the zinc-dependent deaminase superfamily at the beginning of the vertebrate radiation. Other members of the family have arisen in mammals and present a history of complex gene duplications and positive selection. All AID/APOBECs have a characteristic zinc-coordination motif, which forms the core of the catalytic site. The crystal structure of human APOBEC2 shows remarkable similarities to that of the bacterial tRNA-editing enzyme TadA, which suggests a conserved mechanism by which polynucleotides are recognized and deaminated. The AID/APOBECs seem to have diverse roles. AID and the APOBEC3s are DNA mutators, acting in antigen-driven antibody diversification processes and in an innate defense system against retroviruses, respectively. APOBEC1 edits the mRNA for apolipoprotein B, a protein involved in lipid transport. A detailed understanding of the biological roles of the family is still some way off, however, and the functions of some members of the family are completely unknown. Given their ability to mutate DNA, a role for the AID/APOBECs in the onset of cancer has been proposed.
Nicholas O Davidson - One of the best experts on this subject based on the ideXlab platform.
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intestine specific expression of APOBEC 1 rescues apolipoprotein b rna editing and alters chylomicron production in APOBEC1 mice
Journal of Lipid Research, 2012Co-Authors: Valerie Blanc, Susan Kennedy, Yan Xie, Jianyang Luo, Nicholas O DavidsonAbstract:Intestinal apolipoprotein B (apoB) mRNA undergoes C-to-U editing, mediated by the catalytic deaminase APOBEC-1, which results in translation of apoB48. APOBEC1−/− mice produce only apoB100 and secrete larger chylomicron particles than those observed in wild-type (WT) mice. Here we show that transgenic rescue of intestinal APOBEC-1 expression (APOBEC1Int/O) restores C-to-U RNA editing of apoB mRNA in vivo, including the canonical site at position 6666 and also at approximately 20 other newly identified downstream sites present in WT mice. The small intestine of APOBEC1Int/O mice produces only apoB48, and the liver produces only apoB100. Serum chylomicron particles were smaller in APOBEC1Int/O mice compared with those from APOBEC1−/− mice, and the predominant fraction of serum apoB48 in APOBEC1Int/O mice migrated in lipoproteins smaller than chylomicrons, even when these mice were fed a high-fat diet. Because apoB48 arises exclusively from the intestine in APOBEC1Int/O mice and intestinal apoB48 synthesis and secretion rates were comparable to WT mice, we were able to infer the major sites of origin of serum apoB48 in WT mice. Our findings imply that less than 25% of serum apoB48 in WT mice arises from the intestine, with the majority originating from the liver.
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intestine specifiof APOBEC 1 rescues apolipoprotein b rna editing and alters chylomicron production in APOBEC1 mice
2012Co-Authors: Valerie Blanc, Susan Kennedy, Yan Xie, Jianyang Luo, Nicholas O DavidsonAbstract:Intestinal apolipoprotein B (apoB) mRNA under- goes C-to-U editing, mediated by the catalytic deaminase APOBEC-1, which results in translation of apoB48. APOBEC1 / mice produce only apoB100 and secrete larger chylomicron particles than those observed in wild-type (WT) mice. Here we show that transgenic rescue of intestinal APOBEC-1 ex- pression ( APOBEC1 Int/O ) restores C-to-U RNA editing of apoB mRNA in vivo, including the canonical site at position 6666 and also at approximately 20 other newly identifi ed down- stream sites present in WT mice. The small intestine of APOBEC1 Int/O mice produces only apoB48, and the liver pro- duces only apoB100. Serum chylomicron particles were smaller in APOBEC1 Int/O mice compared with those from APOBEC1 / mice, and the predominant fraction of serum apoB48 in APOBEC1 Int/O mice migrated in lipoproteins smaller than chylomicrons, even when these mice were fed a high- fat diet. Because apoB48 arises exclusively from the intes- tine in APOBEC1 Int/O mice and intestinal apoB48 synthesis and secretion rates were comparable to WT mice, we were able to infer the major sites of origin of serum apoB48 in WT mice. Our fi ndings imply that less than 25% of serum apoB48 in WT mice arises from the intestine, with the ma- jority originating from the liver. —Blanc, V., Y. Xie, J. Luo, S. Kennedy, and N. O. Davidson. Intestine-specifi of APOBEC-1 rescues apolipoprotein B RNA editing and al- ters chylomicron production in APOBEC1 / mice. J. Lipid Res. 2012. 53: 2643-2655.
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decreased expression of cholesterol 7α hydroxylase and altered bile acid metabolism in APOBEC 1 mice lead to increased gallstone susceptibility
Journal of Biological Chemistry, 2009Co-Authors: Valerie Blanc, Thomas A Kerr, Susan Kennedy, Elizabeth P Newberry, Nicholas O DavidsonAbstract:Quantitative trait mapping in mice identified a susceptibility locus for gallstones (Lith6) spanning the APOBEC-1 locus, the structural gene encoding the RNA-specific cytidine deaminase responsible for production of apolipoprotein B48 in mammalian small intestine and rodent liver. This observation prompted us to compare dietary gallstone susceptibility in APOBEC-1−/− mice and congenic C57BL/6 wild type controls. When fed a lithogenic diet (LD) for 2 weeks, 90% APOBEC-1−/− mice developed solid gallstones in comparison with 16% wild type controls. LD-fed APOBEC-1−/− mice demonstrated increased biliary cholesterol secretion as well as increased cholesterol saturation and bile acid hydrophobicity indices. These changes occurred despite a relative decrease in cholesterol absorption in LD-fed APOBEC-1−/− mice. Among the possible mechanisms to account for this phenotype, expression of Cyp7a1 mRNA and protein were significantly decreased in chow-fed APOBEC-1−/− mice, decreasing further in LD-fed animals. Cyp7a1 transcription in hepatocyte nuclei, however, was unchanged in APOBEC-1−/− mice, excluding transcriptional repression as a potential mechanism for decreased Cyp7a1 expression. We demonstrated that APOBEC-1 binds to AU-rich regions of the 3′-untranslated region of the Cyp7a1 transcript, containing the UUUN(A/U)U consensus motif, using both UV cross-linking to recombinant APOBEC-1 and in vivo RNA co-immunoprecipitation. In vivo APOBEC-1-dependent modulation of Cyp7a1 expression was further confirmed following adenovirus-APOBEC-1 administration to chow-fed APOBEC-1−/− mice, which rescued Cyp7a1 gene expression. Taken together, the findings suggest that the AU-rich RNA binding-protein APOBEC-1 mediates post-transcriptional regulation of murine Cyp7a1 expression and influences susceptibility to diet-induced gallstone formation.
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APOBEC 1 protects intestine from radiation injury through posttranscriptional regulation of cyclooxygenase 2 expression
Gastroenterology, 2004Co-Authors: Shrikant Anant, Stephen G Young, Debnath Mukhopadhyay, Nabendu Murmu, Courtney W Houchen, Terrence E Riehl, Aubrey R Morrison, William F Stenson, Nicholas O DavidsonAbstract:Background & Aims: This study aimed to determine the role of the RNA binding protein APOBEC-1 in radioprotection of the intestine. Methods: APOBEC-1-deleted mice ( APOBEC -1 −/− ) and wild-type controls were treated with 12 Gy of whole-body γ-irradiation in a cesium irradiator. The number of surviving intestinal crypts was assessed 3.5 days after irradiation by using a clonogenic assay. Cyclooxygenase-2 messenger RNA and protein expression were determined by real-time polymerase chain reaction and Western blot, respectively. RNA stability was studied by examining the turnover of a chimeric transcript containing the cyclooxygenase-2 3′ untranslated region cloned downstream of luciferase complementary DNA. APOBEC-1 binding to the cyclooxygenase-2 3′ untranslated region was studied by electrophoretic mobility shift and UV crosslinking assays. Results: After γ-irradiation, the survival of intestinal stem cells decreased significantly in APOBEC -1 −/− mice. In wild-type mice treated with lipopolysaccharide before γ-irradiation, intestinal stem cells were protected by marked increases in prostaglandin E 2 mediated by cyclooxygenase-2. No such effect was observed in the APOBEC -1 −/− mice. The mechanism of this radioprotective effect involves the binding of APOBEC-1 to AU-rich sequences in the first 60 nucleotides of the 3′ untranslated region of cyclooxygenase-2. Upon binding to the AU-rich sequences, APOBEC-1 stabilizes cyclooxygenase-2 messenger RNA. This stabilization process does not seem to be mediated by p38 mitogen-activated protein kinase pathways. Conclusions: Lipopolysaccharide increases intestinal stem cell survival through APOBEC-1-mediated regulation of cyclooxygenase-2 messenger RNA stability.
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cytidine deamination of retroviral dna by diverse APOBEC proteins
Current Biology, 2004Co-Authors: Kate N Bishop, Rebecca K Holmes, Ann M Sheehy, Nicholas O Davidson, Soojin Cho, Michael H MalimAbstract:The human cytidine deaminase APOBEC3G edits both nascent human immunodeficiency virus (HIV) and murine leukemia virus (MLV) reverse transcripts, resulting in loss of infectivity. The HIV Vif protein is able to protect both viruses from this innate restriction to infection. Here, we demonstrate that a number of other APOBEC family members from both humans and rodents can mediate anti-HIV effects, through cytidine deamination. Three of these, rat APOBEC1, mouse APOBEC3, and human APOBEC3B, are able to inhibit HIV infectivity even in the presence of Vif. Like APOBEC3G, human APOBEC3F preferentially restricts vif-deficient virus. Indeed, the mutation spectra and expression profile found for APOBEC3F indicate that this enzyme, together with APOBEC3G, accounts for the G to A hypermutation of proviruses described in HIV-infected individuals. Surprisingly, although MLV infectivity is acutely reduced by APOBEC3G, no other family member tested here had this effect. It is especially interesting that although both rodent APOBECs markedly diminish wild-type HIV infectivity, MLV is resistant to these proteins. This implies that MLV may have evolved to avoid deamination by mouse APOBEC3. Overall, our findings show that although APOBEC family members are highly related, they exhibit significantly distinct antiviral characteristics that may provide new insights into host-pathogen interactions.
Terumasa Ikeda - One of the best experts on this subject based on the ideXlab platform.
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intrinsic immunity against retrotransposons by APOBEC cytidine deaminases
Frontiers in Microbiology, 2013Co-Authors: Atsushi Koito, Terumasa IkedaAbstract:Over 40% of the human genome is recognizable as having been derived from ancient retroelements, transported by an intracellular copy-and-paste process involving an RNA intermediate, with an additional few percent classified as DNA transposable elements. Endogenous retroviruses are long terminal repeat (LTR)-type retroelements that account for ~8% of human genomic DNA. Non-LTR members are present at extremely high copy numbers, with ~17% of the human genome consisting of long interspersed nuclear elements (LINEs). These LINEs modify vertebrate genomes not only through insertions, but also by the indirect replication of non-autonomous retrotransposons, such as short interspersed nuclear elements. As expected, vertebrate intrinsic immunity has evolved to support a balance between retroelement insertions that confer beneficial genetic diversity and those that cause deleterious gene disruptions. The mammalian cytidine deaminases encoded by the APOBEC3 genes can restrict a broad number of exogenous pathogens, such as exogenous retroviruses, and the mobility of endogenous retroelements. Furthermore, APOBEC1 from a variety of mammalian species, which mediates the cytidine (C) to uridine (U) deamination of apolipoprotein B (apoB) mRNA, a protein involved in lipid transport, also plays a role in controlling mobile elements. These mammalian apoB mRNA-editing, catalytic polypeptide (APOBEC) cytidine deaminases, which can bind to single-stranded DNA (ssDNA) as well as RNA, are able to insert mutations into ssDNA and/or RNA as a result of their ability to deaminate C to U. While these APOBEC cytidine deaminases with DNA mutagenic activity can be deleterious to cells, their biological modifications, such as protein-protein interactions and subcellular localization, in addition to their ability to bind to RNA, appear to have conferred a role for APOBECs as a cellular defense system against retroviruses and retroelements. In support of this notion, the expansion of the single APOBEC3 gene in mice to the seven APOBEC3 genes found in primates apparently correlates with the significant enhancement of the restriction of endogenous retroelements seen in primates, including humans. This review discusses the current understanding of the mechanism of action of APOBEC cytidine deaminases and attempts to summarize their roles in controlling retrotransposons.
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intrinsic restriction activity by apob mrna editing enzyme APOBEC1 against the mobility of retroelements
Retrovirology, 2011Co-Authors: Atsushi Koito, Terumasa IkedaAbstract:A large portion of the mammalian genome is derived from ancient transposable elements. Retroelements, transported by an intracellular copy-and-paste process involving an RNA intermediate (retrotransposition), constitute a majority of these mobile genetic elements. Endogenous retroviruses are LTR-type retroelements accounting for around 8% of human or murine genomic DNA. Non-LTR members are present in extremely high copy numbers; with LINE-1 contributing to nearly 40% of human and murine genomes. These LINE-1 elements modify mammalian genomes not only through insertions, but also by indirect replication of nonautonomous retrotransposons such as SINEs. As expected, cellular machineries of vertebrate’ si nnate immunity have evolved to support a balance between retroelement insertions that cause deleterious gene disruptions and those that confer beneficial genetic diversity. The ability of mammalian cytidine deaminases encoded by the APOBEC3 (A3) genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including MLV and HIV-1, is now well established. The RNA editing family member apolipoprotein B (apo B)editing catalytic subunit 1 (APOBEC1; A1) from a variety of mammalian species, a protein involved in lipid transport and which mediates C-to-U deamination of mRNA for apo B, has also been shown to modify a range of exogenous retroviruses, but it’s activity against endogenous retroelements remains unclear. Here we show that A1 family proteins can also reduce the mobility and infectivity potential of LINE-1 and LTR retrotransposons (or endogenous retroviruses) such as IAP and MusD sequences. The anti-L1 activity of A1 was mainly mediated by a deamination-independent mechanism with inhibition at step prior to the integration, and was not affected by nuclear localization of the proteins. In contrast, A1 inhibits the replication of murine IAP and MusD through a DNA deamination-dependent mechanism. Thus, the AID/APOBEC family proteins including A1s employ multiple mechanisms to regulate the mobility of autonomous retrotransposons in a wide range of mammalian species.
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Intrinsic restriction activity by apolipoprotein B mRNA editing enzyme APOBEC1 against the mobility of autonomous retrotransposons
Nucleic acids research, 2011Co-Authors: Terumasa Ikeda, Khaled H. Abd El Galil, Kenzo Tokunaga, Kazuhiko Maeda, Tetsutaro Sata, Nobuo Sakaguchi, Thierry Heidmann, Atsushi KoitoAbstract:The ability of mammalian cytidine deaminases encoded by the APOBEC3 (A3) genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including murine leukemia virus and human immunodeficiency virus (HIV)-1, is now well established. The RNA editing family member apolipoprotein B (apo B)-editing catalytic subunit 1 (APOBEC1; A1) from a variety of mammalian species, a protein involved in lipid transport and which mediates C-U deamination of mRNA for apo B, has also been shown to modify a range of exogenous retroviruses, but its activity against endogenous retroelements remains unclear. Here, we show in cell culture-based retrotransposition assays that A1 family proteins from multiple mammalian species can also reduce the mobility and infectivity potential of LINE-1 (long interspersed nucleotide sequence-1, L1) and long-terminal repeats (LTRs) retrotransposons (or endogenous retroviruses), such as murine intracisternal A-particle (IAP) and MusD sequences. The anti-L1 activity of A1 was mainly mediated by a deamination-independent mechanism, and was not affected by subcellular localization of the proteins. In contrast, the inhibition of LTR-retrotransposons appeared to require the deaminase activity of A1 proteins. Thus, the AID/APOBEC family proteins including A1s employ multiple mechanisms to regulate the mobility of autonomous retrotransposons in several mammalian species.
Atsushi Koito - One of the best experts on this subject based on the ideXlab platform.
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intrinsic immunity against retrotransposons by APOBEC cytidine deaminases
Frontiers in Microbiology, 2013Co-Authors: Atsushi Koito, Terumasa IkedaAbstract:Over 40% of the human genome is recognizable as having been derived from ancient retroelements, transported by an intracellular copy-and-paste process involving an RNA intermediate, with an additional few percent classified as DNA transposable elements. Endogenous retroviruses are long terminal repeat (LTR)-type retroelements that account for ~8% of human genomic DNA. Non-LTR members are present at extremely high copy numbers, with ~17% of the human genome consisting of long interspersed nuclear elements (LINEs). These LINEs modify vertebrate genomes not only through insertions, but also by the indirect replication of non-autonomous retrotransposons, such as short interspersed nuclear elements. As expected, vertebrate intrinsic immunity has evolved to support a balance between retroelement insertions that confer beneficial genetic diversity and those that cause deleterious gene disruptions. The mammalian cytidine deaminases encoded by the APOBEC3 genes can restrict a broad number of exogenous pathogens, such as exogenous retroviruses, and the mobility of endogenous retroelements. Furthermore, APOBEC1 from a variety of mammalian species, which mediates the cytidine (C) to uridine (U) deamination of apolipoprotein B (apoB) mRNA, a protein involved in lipid transport, also plays a role in controlling mobile elements. These mammalian apoB mRNA-editing, catalytic polypeptide (APOBEC) cytidine deaminases, which can bind to single-stranded DNA (ssDNA) as well as RNA, are able to insert mutations into ssDNA and/or RNA as a result of their ability to deaminate C to U. While these APOBEC cytidine deaminases with DNA mutagenic activity can be deleterious to cells, their biological modifications, such as protein-protein interactions and subcellular localization, in addition to their ability to bind to RNA, appear to have conferred a role for APOBECs as a cellular defense system against retroviruses and retroelements. In support of this notion, the expansion of the single APOBEC3 gene in mice to the seven APOBEC3 genes found in primates apparently correlates with the significant enhancement of the restriction of endogenous retroelements seen in primates, including humans. This review discusses the current understanding of the mechanism of action of APOBEC cytidine deaminases and attempts to summarize their roles in controlling retrotransposons.
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intrinsic restriction activity by apob mrna editing enzyme APOBEC1 against the mobility of retroelements
Retrovirology, 2011Co-Authors: Atsushi Koito, Terumasa IkedaAbstract:A large portion of the mammalian genome is derived from ancient transposable elements. Retroelements, transported by an intracellular copy-and-paste process involving an RNA intermediate (retrotransposition), constitute a majority of these mobile genetic elements. Endogenous retroviruses are LTR-type retroelements accounting for around 8% of human or murine genomic DNA. Non-LTR members are present in extremely high copy numbers; with LINE-1 contributing to nearly 40% of human and murine genomes. These LINE-1 elements modify mammalian genomes not only through insertions, but also by indirect replication of nonautonomous retrotransposons such as SINEs. As expected, cellular machineries of vertebrate’ si nnate immunity have evolved to support a balance between retroelement insertions that cause deleterious gene disruptions and those that confer beneficial genetic diversity. The ability of mammalian cytidine deaminases encoded by the APOBEC3 (A3) genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including MLV and HIV-1, is now well established. The RNA editing family member apolipoprotein B (apo B)editing catalytic subunit 1 (APOBEC1; A1) from a variety of mammalian species, a protein involved in lipid transport and which mediates C-to-U deamination of mRNA for apo B, has also been shown to modify a range of exogenous retroviruses, but it’s activity against endogenous retroelements remains unclear. Here we show that A1 family proteins can also reduce the mobility and infectivity potential of LINE-1 and LTR retrotransposons (or endogenous retroviruses) such as IAP and MusD sequences. The anti-L1 activity of A1 was mainly mediated by a deamination-independent mechanism with inhibition at step prior to the integration, and was not affected by nuclear localization of the proteins. In contrast, A1 inhibits the replication of murine IAP and MusD through a DNA deamination-dependent mechanism. Thus, the AID/APOBEC family proteins including A1s employ multiple mechanisms to regulate the mobility of autonomous retrotransposons in a wide range of mammalian species.
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Intrinsic restriction activity by apolipoprotein B mRNA editing enzyme APOBEC1 against the mobility of autonomous retrotransposons
Nucleic acids research, 2011Co-Authors: Terumasa Ikeda, Khaled H. Abd El Galil, Kenzo Tokunaga, Kazuhiko Maeda, Tetsutaro Sata, Nobuo Sakaguchi, Thierry Heidmann, Atsushi KoitoAbstract:The ability of mammalian cytidine deaminases encoded by the APOBEC3 (A3) genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including murine leukemia virus and human immunodeficiency virus (HIV)-1, is now well established. The RNA editing family member apolipoprotein B (apo B)-editing catalytic subunit 1 (APOBEC1; A1) from a variety of mammalian species, a protein involved in lipid transport and which mediates C-U deamination of mRNA for apo B, has also been shown to modify a range of exogenous retroviruses, but its activity against endogenous retroelements remains unclear. Here, we show in cell culture-based retrotransposition assays that A1 family proteins from multiple mammalian species can also reduce the mobility and infectivity potential of LINE-1 (long interspersed nucleotide sequence-1, L1) and long-terminal repeats (LTRs) retrotransposons (or endogenous retroviruses), such as murine intracisternal A-particle (IAP) and MusD sequences. The anti-L1 activity of A1 was mainly mediated by a deamination-independent mechanism, and was not affected by subcellular localization of the proteins. In contrast, the inhibition of LTR-retrotransposons appeared to require the deaminase activity of A1 proteins. Thus, the AID/APOBEC family proteins including A1s employ multiple mechanisms to regulate the mobility of autonomous retrotransposons in several mammalian species.