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Tasuku Honjo - One of the best experts on this subject based on the ideXlab platform.
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rna editing of hepatitis b virus transcripts by activation induced Cytidine Deaminase
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Tasuku Honjo, Guoxin Liang, Kouichi Kitamura, Sajeda Chowdhury, Miki Koura, Zhe Wang, Guangyan Liu, Kousho Wakae, Masamichi MuramatsuAbstract:Activation-induced Cytidine Deaminase (AID) is essential for the somatic hypermutation (SHM) and class-switch recombination (CSR) of Ig genes. The mechanism by which AID triggers SHM and CSR has been explained by two distinct models. In the DNA deamination model, AID converts Cytidine bases in DNA into uridine. The uridine is recognized by the DNA repair system, which produces DNA strand breakages and point mutations. In the alternative model, RNA edited by AID is responsible for triggering CSR and SHM. However, RNA deamination by AID has not been demonstrated. Here we found that C-to-T and G-to-A mutations accumulated in hepatitis B virus (HBV) nucleocapsid DNA when AID was expressed in HBV-replicating hepatic cell lines. AID expression caused C-to-T mutations in the nucleocapsid DNA of RNase H-defective HBV, which does not produce plus-strand viral DNA. Furthermore, the RT-PCR products of nucleocapsid viral RNA from AID-expressing cells exhibited significant C-to-T mutations, whereas viral RNAs outside the nucleocapsid did not accumulate C-to-U mutations. Moreover, AID was packaged within the nucleocapsid by forming a ribonucleoprotein complex with HBV RNA and the HBV polymerase protein. The encapsidation of the AID protein with viral RNA and DNA provides an efficient environment for evaluating AID’s RNA and DNA deamination activities. A bona fide RNA-editing enzyme, apolipoprotein B mRNA editing catalytic polypeptide 1, induced a similar level of C-to-U mutations in nucleocapsid RNA as AID. Taken together, the results indicate that AID can deaminate the nucleocapsid RNA of HBV.
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decrease in topoisomerase i is responsible for activation induced Cytidine Deaminase aid dependent somatic hypermutation
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Maki Kobayashi, Yoko Kitawaki, Zahra Sabouri, Somayeh Sabouri, Takaya Abe, Hiroshi Kiyonari, Tasuku HonjoAbstract:Somatic hypermutation (SHM) and class-switch recombination (CSR) of the Ig gene require both the transcription of the locus and the expression of activation-induced Cytidine Deaminase (AID). During CSR, AID decreases the amount of topoisomerase I (Top1); this decrease alters the DNA structure and induces cleavage in the S region. Similarly, Top1 is involved in transcription-associated mutation at dinucleotide repeats in yeast and in triplet-repeat contraction in mammals. Here, we report that the AID-induced decrease in Top1 is critical for SHM. Top1 knockdown or haploinsufficiency enhanced SHM, whereas Top1 overexpression down-regulated it. A specific Top1 inhibitor, camptothecin, suppressed SHM, indicating that Top1's activity is required for DNA cleavage. Nonetheless, suppression of transcription abolished SHM, even in cells with Top1 knockdown, suggesting that transcription is critical. These results are consistent with a model proposed for CSR and triplet instability, in which transcription-induced non-B structure formation is enhanced by Top1 reduction and provides the target for irreversible cleavage by Top1. We speculate that the mechanism for transcription-coupled genome instability was adopted to generate immune diversity when AID evolved.
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helicobacter pylori infection triggers aberrant expression of activation induced Cytidine Deaminase in gastric epithelium
Nature Medicine, 2007Co-Authors: Yuko Matsumoto, Hiroyuki Marusawa, Kazuo Kinoshita, Yoko Endo, Tadayuki Kou, Toshiyuki Morisawa, Takeshi Azuma, Ilmi Okazaki, Tasuku Honjo, Tsutomu ChibaAbstract:Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced Cytidine Deaminase (AID), a member of the Cytidine-Deaminase family that acts as a DNA- and RNA-editing enzyme, via the IkappaB kinase-dependent nuclear factor-kappaB activation pathway. H. pylori-mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori-associated gastric carcinogenesis.
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helicobacter pylori infection triggers aberrant expression of activation induced Cytidine Deaminase in gastric epithelium
Nature Medicine, 2007Co-Authors: Yuko Matsumoto, Hiroyuki Marusawa, Kazuo Kinoshita, Yoko Endo, Toshiyuki Morisawa, Takeshi Azuma, Ilmi Okazaki, Tasuku Honjo, Tsutomu ChibaAbstract:Helicobacter pylori infection triggers aberrant expression of activation-induced Cytidine Deaminase in gastric epithelium
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activation induced Cytidine Deaminase aid promotes b cell lymphomagenesis in emu cmyc transgenic mice
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Ai Kotani, Kazuo Kinoshita, Ilmi Okazaki, Masamichi Muramatsu, Hitoshi Nagaoka, Naoki Kakazu, Tatsuaki Tsuruyama, Daisuke Yabe, Tasuku HonjoAbstract:Activation-induced Cytidine Deaminase (AID), which is essential to both class switch recombination and somatic hypermutation of the Ig gene, is expressed in many types of human B cell lymphoma/leukemia. AID is a potent mutator because it is involved in DNA breakage not only of Ig but also of other genes, including proto-oncogenes. Recent studies suggest that AID is required for chromosomal translocation involving cmyc and Ig loci. However, it is unclear whether AID plays other roles in tumorigenesis. We examined the effect of AID deficiency on the generation of surface Ig-positive B cell lymphomas in Emu-cmyc transgenic mice. Almost all lymphomas that developed in AID-deficient transgenic mice were pre-B cell lymphomas, whereas control transgenic mice had predominantly B cell lymphomas, indicating that AID is required for development of B but not pre-B cell lymphomas from cmyc overexpressing tumor progenitors. Thus, AID may play multiple roles in B cell lymphomagenesis.
Masamichi Muramatsu - One of the best experts on this subject based on the ideXlab platform.
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interleukin 1 and tumor necrosis factor α trigger restriction of hepatitis b virus infection via a Cytidine Deaminase activation induced Cytidine Deaminase aid
Journal of Biological Chemistry, 2013Co-Authors: Koichi Watashi, Hiroyuki Marusawa, Masamichi Muramatsu, Guoxin Liang, Masashi Iwamoto, Nanako Uchida, Takuji Daito, Kouichi Kitamura, Hirofumi Ohashi, Tomoko KiyoharaAbstract:Virus infection is restricted by intracellular immune responses in host cells, and this is typically modulated by stimulation of cytokines. The cytokines and host factors that determine the host cell restriction against hepatitis B virus (HBV) infection are not well understood. We screened 36 cytokines and chemokines to determine which were able to reduce the susceptibility of HepaRG cells to HBV infection. Here, we found that pretreatment with IL-1β and TNFα remarkably reduced the host cell susceptibility to HBV infection. This effect was mediated by activation of the NF-κB signaling pathway. A Cytidine Deaminase, activation-induced Cytidine Deaminase (AID), was up-regulated by both IL-1β and TNFα in a variety of hepatocyte cell lines and primary human hepatocytes. Another Deaminase APOBEC3G was not induced by these proinflammatory cytokines. Knockdown of AID expression impaired the anti-HBV effect of IL-1β, and overexpression of AID antagonized HBV infection, suggesting that AID was one of the responsible factors for the anti-HBV activity of IL-1/TNFα. Although AID induced hypermutation of HBV DNA, this activity was dispensable for the anti-HBV activity. The antiviral effect of IL-1/TNFα was also observed on different HBV genotypes but not on hepatitis C virus. These results demonstrate that proinflammatory cytokines IL-1/TNFα trigger a novel antiviral mechanism involving AID to regulate host cell permissiveness to HBV infection. Background: Cytokines and host factors triggering innate immunity against hepatitis B virus (HBV) are not well understood. Results: IL-1 and TNFα induced Cytidine Deaminase AID, an anti-HBV host factor, and reduced HBV infection into hepatocytes. Conclusion: IL-1/TNFα reduced host susceptibility to HBV infection through AID up-regulation. Significance: Proinflammatory cytokines modulate HBV infection through a novel innate immune pathway involving AID.
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interleukin 1 and tumor necrosis factor α trigger restriction of hepatitis b virus infection via a Cytidine Deaminase activation induced Cytidine Deaminase aid
Journal of Biological Chemistry, 2013Co-Authors: Koichi Watashi, Hiroyuki Marusawa, Masamichi Muramatsu, Guoxin Liang, Masashi Iwamoto, Nanako Uchida, Takuji Daito, Kouichi Kitamura, Hirofumi Ohashi, Tomoko KiyoharaAbstract:Abstract Virus infection is restricted by intracellular immune responses in host cells and this is typically modulated by stimulation of cytokines. The cytokines and host factors which determine the host cell restriction against hepatitis B virus (HBV) infection are not well understood. We screened 36 cytokines and chemokines to determine which were able to reduce the susceptibility of HepaRG cells to HBV infection. Here, we found that pretreatment with IL-1β and TNFα remarkably reduced the host cell susceptibility to HBV infection. This effect was mediated by activation of the NF-κB signaling pathway. A Cytidine Deaminase, activation-induced Cytidine Deaminase (AID), was upregulated by both IL-1β and TNFα in a variety of hepatocyte cell lines and primary human hepatocytes. Another Deaminase APOBEC3G was not induced by these proinflammatory cytokines. Knocking down of AID expression impaired the anti-HBV effect of IL-1β, and overexpression of AID antagonized HBV infection, suggesting that AID was one of the responsible factors for the anti-HBV activity of IL-1/TNFα. Although AID induced hypermutation of HBV DNA, this activity was dispensable for the anti-HBV activity. The antiviral effect of IL-1/TNFα was also observed on different HBV genotypes, but not on hepatitis C virus. These results demonstrate that proinflammatory cytokines IL-1/TNFα trigger a novel antiviral mechanism involving AID to regulate host cell permissiveness to HBV infection.
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concerted action of activation induced Cytidine Deaminase and uracil dna glycosylase reduces covalently closed circular dna of duck hepatitis b virus
FEBS Letters, 2013Co-Authors: Sajeda Chowdhury, Kouichi Kitamura, Miyuki Simadu, Miki Koura, Masamichi MuramatsuAbstract:Covalently closed circular DNA (cccDNA) forms a template for the replication of hepatitis B virus (HBV) and duck HBV (DHBV). Recent studies suggest that activation-induced Cytidine Deaminase (AID) functions in innate immunity, although its molecular mechanism of action remains unclear, particularly regarding HBV restriction. Here we demonstrated that overexpression of chicken AID caused hypermutation and reduction of DHBV cccDNA levels. Inhibition of uracil-DNA glycosylase (UNG) by UNG inhibitor protein (UGI) abolished AID-induced cccDNA reduction, suggesting that the AID/UNG pathway triggers the degradation of cccDNA via cytosine deamination and uracil excision.
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rna editing of hepatitis b virus transcripts by activation induced Cytidine Deaminase
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Tasuku Honjo, Guoxin Liang, Kouichi Kitamura, Sajeda Chowdhury, Miki Koura, Zhe Wang, Guangyan Liu, Kousho Wakae, Masamichi MuramatsuAbstract:Activation-induced Cytidine Deaminase (AID) is essential for the somatic hypermutation (SHM) and class-switch recombination (CSR) of Ig genes. The mechanism by which AID triggers SHM and CSR has been explained by two distinct models. In the DNA deamination model, AID converts Cytidine bases in DNA into uridine. The uridine is recognized by the DNA repair system, which produces DNA strand breakages and point mutations. In the alternative model, RNA edited by AID is responsible for triggering CSR and SHM. However, RNA deamination by AID has not been demonstrated. Here we found that C-to-T and G-to-A mutations accumulated in hepatitis B virus (HBV) nucleocapsid DNA when AID was expressed in HBV-replicating hepatic cell lines. AID expression caused C-to-T mutations in the nucleocapsid DNA of RNase H-defective HBV, which does not produce plus-strand viral DNA. Furthermore, the RT-PCR products of nucleocapsid viral RNA from AID-expressing cells exhibited significant C-to-T mutations, whereas viral RNAs outside the nucleocapsid did not accumulate C-to-U mutations. Moreover, AID was packaged within the nucleocapsid by forming a ribonucleoprotein complex with HBV RNA and the HBV polymerase protein. The encapsidation of the AID protein with viral RNA and DNA provides an efficient environment for evaluating AID’s RNA and DNA deamination activities. A bona fide RNA-editing enzyme, apolipoprotein B mRNA editing catalytic polypeptide 1, induced a similar level of C-to-U mutations in nucleocapsid RNA as AID. Taken together, the results indicate that AID can deaminate the nucleocapsid RNA of HBV.
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activation induced Cytidine Deaminase aid promotes b cell lymphomagenesis in emu cmyc transgenic mice
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Ai Kotani, Kazuo Kinoshita, Ilmi Okazaki, Masamichi Muramatsu, Hitoshi Nagaoka, Naoki Kakazu, Tatsuaki Tsuruyama, Daisuke Yabe, Tasuku HonjoAbstract:Activation-induced Cytidine Deaminase (AID), which is essential to both class switch recombination and somatic hypermutation of the Ig gene, is expressed in many types of human B cell lymphoma/leukemia. AID is a potent mutator because it is involved in DNA breakage not only of Ig but also of other genes, including proto-oncogenes. Recent studies suggest that AID is required for chromosomal translocation involving cmyc and Ig loci. However, it is unclear whether AID plays other roles in tumorigenesis. We examined the effect of AID deficiency on the generation of surface Ig-positive B cell lymphomas in Emu-cmyc transgenic mice. Almost all lymphomas that developed in AID-deficient transgenic mice were pre-B cell lymphomas, whereas control transgenic mice had predominantly B cell lymphomas, indicating that AID is required for development of B but not pre-B cell lymphomas from cmyc overexpressing tumor progenitors. Thus, AID may play multiple roles in B cell lymphomagenesis.
Kazuo Kinoshita - One of the best experts on this subject based on the ideXlab platform.
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helicobacter pylori infection triggers aberrant expression of activation induced Cytidine Deaminase in gastric epithelium
Nature Medicine, 2007Co-Authors: Yuko Matsumoto, Hiroyuki Marusawa, Kazuo Kinoshita, Yoko Endo, Tadayuki Kou, Toshiyuki Morisawa, Takeshi Azuma, Ilmi Okazaki, Tasuku Honjo, Tsutomu ChibaAbstract:Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced Cytidine Deaminase (AID), a member of the Cytidine-Deaminase family that acts as a DNA- and RNA-editing enzyme, via the IkappaB kinase-dependent nuclear factor-kappaB activation pathway. H. pylori-mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori-associated gastric carcinogenesis.
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helicobacter pylori infection triggers aberrant expression of activation induced Cytidine Deaminase in gastric epithelium
Nature Medicine, 2007Co-Authors: Yuko Matsumoto, Hiroyuki Marusawa, Kazuo Kinoshita, Yoko Endo, Toshiyuki Morisawa, Takeshi Azuma, Ilmi Okazaki, Tasuku Honjo, Tsutomu ChibaAbstract:Helicobacter pylori infection triggers aberrant expression of activation-induced Cytidine Deaminase in gastric epithelium
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expression of activation induced Cytidine Deaminase in human hepatocytes during hepatocarcinogenesis
International Journal of Cancer, 2007Co-Authors: Tadayuki Kou, Hiroyuki Marusawa, Kazuo Kinoshita, Yoko Endo, Ilmi Okazaki, Yoshihide Ueda, Yuzo Kodama, Hironori Haga, Iwao Ikai, Tsutomu ChibaAbstract:Activation-induced Cytidine Deaminase (AID) plays a role as a genome mutator in activated B cells, and inappropriate expression of AID has been implicated in the immunopathological phenotype of human B-cell malignancies. Notably, we found that the transgenic mice overexpressing AID developed lung adenocarcinoma and hepatocellular carcinoma (HCC), suggesting that ectopic expression of AID can lead to tumorigenesis in epithelial tissues as well. To examine the involvement of AID in the development of human HCC, we analyzed the AID expression and its correlation with mutation frequencies of the p53 gene in liver tissues from 51 patients who underwent resection of primary HCCs. The specific expression, inducibility by cytokine stimulation and mutagenic activity of AID were investigated in cultured human hepatocytes. Only trace amounts of AID transcripts were detected in the normal liver; however, endogenous AID was significantly upregulated in both HCC and surrounding noncancerous liver tissues with underlying chronic hepatitis or liver cirrhosis (p < 0.05). Most liver tissues with underlying chronic inflammation with endogenous AID upregulation already contained multiple genetic changes in the p53 gene. In both hepatoma cell lines and cultured human primary hepatocytes, the expression of AID was substantially induced by TGF-beta stimulation. Aberrant activation of AID in hepatocytes resulted in accumulation of multiple genetic alterations in the p53 gene. Our findings suggest that the aberrant expression of AID is observed in human hepatocytes with several pathological settings, including chronic liver disease and HCC, which might enhance the genetic susceptibility to mutagenesis leading to hepatocarcinogenesis.
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activation induced Cytidine Deaminase aid promotes b cell lymphomagenesis in emu cmyc transgenic mice
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Ai Kotani, Kazuo Kinoshita, Ilmi Okazaki, Masamichi Muramatsu, Hitoshi Nagaoka, Naoki Kakazu, Tatsuaki Tsuruyama, Daisuke Yabe, Tasuku HonjoAbstract:Activation-induced Cytidine Deaminase (AID), which is essential to both class switch recombination and somatic hypermutation of the Ig gene, is expressed in many types of human B cell lymphoma/leukemia. AID is a potent mutator because it is involved in DNA breakage not only of Ig but also of other genes, including proto-oncogenes. Recent studies suggest that AID is required for chromosomal translocation involving cmyc and Ig loci. However, it is unclear whether AID plays other roles in tumorigenesis. We examined the effect of AID deficiency on the generation of surface Ig-positive B cell lymphomas in Emu-cmyc transgenic mice. Almost all lymphomas that developed in AID-deficient transgenic mice were pre-B cell lymphomas, whereas control transgenic mice had predominantly B cell lymphomas, indicating that AID is required for development of B but not pre-B cell lymphomas from cmyc overexpressing tumor progenitors. Thus, AID may play multiple roles in B cell lymphomagenesis.
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de novo protein synthesis is required for activation induced Cytidine Deaminase dependent dna cleavage in immunoglobulin class switch recombination
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Nasim A Begum, Kazuo Kinoshita, Masamichi Muramatsu, Hitoshi Nagaoka, Reiko Shinkura, Tasuku HonjoAbstract:Activation-induced Cytidine Deaminase is required for the DNA cleavage step of Ig class switch recombination (CSR). However, its molecular mechanism is controversial. RNA-editing hypothesis postulates that activation-induced Cytidine Deaminase deaminates cytosine in an unknown mRNA to generate a new mRNA encoding an endonuclease for CSR and thus predicts that DNA cleavage depends on de novo protein synthesis. On the other hand, DNA deamination hypothesis proposes that DNA cleavage is initiated by cytosine deamination in DNA, followed by uracil removal by uracil DNA glycosylase. By using the chromatin immunoprecipitation assay to detect γ-H2AX focus formation as a marker for DNA cleavage, we found that cycloheximide inhibited DNA cleavage in the Ig heavy-chain locus during CSR. Requirement of protein synthesis in the DNA cleavage step of CSR strengthens the RNA-editing hypothesis.
Myron F Goodman - One of the best experts on this subject based on the ideXlab platform.
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ganp mediated recruitment of activation induced Cytidine Deaminase to cell nuclei and to immunoglobulin variable region dna
Journal of Biological Chemistry, 2010Co-Authors: Kazuhiko Maeda, Phuong Pham, Myron F Goodman, Shailendra Kumar Singh, Kazufumi Eda, Masahiro Kitabatake, Nobuo SakaguchiAbstract:AID (activation-induced Cytidine Deaminase) catalyzes transcription-dependent deamination of C → U in immunoglobulin variable (IgV) regions to initiate somatic hypermutation (SHM) in germinal center B-cells. SHM is essential in generating high affinity antibodies. Here we show that when coexpressed with GANP (germinal center-associated nuclear protein) in COS-7 cells, AID is transported from the cytoplasm and concentrated in the nucleus. GANP forms a complex with AID in cotransfected cells in vivo and in vitro. We have isolated AID mutants that bind with reduced affinity to GANP compared with wild type AID. One of these mutants, AID (D143A) binds GANP with a 10-fold lower affinity compared with wild type AID yet retains substantial C-deamination activity in vitro. Mutant AID (D143A) remains localized predominantly in the cytoplasm when coexpressed with GANP. Exogenous expression of GANP in Ramos B-cells promotes binding of AID to IgV DNA and mRNA and increases SHM frequency. These data suggest that GANP may serve as an essential link required to transport AID to B-cell nuclei and to target AID to actively transcribed IgV regions.
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biochemical basis of immunological and retroviral responses to dna targeted cytosine deamination by activation induced Cytidine Deaminase and apobec3g
Journal of Biological Chemistry, 2009Co-Authors: Linda Chelico, Phuong Pham, John Petruska, Myron F GoodmanAbstract:Activation-induced Cytidine Deaminase (AID) and APOBEC3G catalyze deamination of cytosine to uracil on single-stranded DNA, thereby setting in motion a regulated hypermutagenic process essential for human well-being. However, if regulation fails, havoc ensues. AID plays a central role in the synthesis of high affinity antibodies, and APOBEC3G inactivates human immunodeficiency virus-1. This minireview highlights biochemical and structural properties of AID and APOBEC3G, showing how studies using the purified enzymes provide valuable insight into the considerably more complex biology governing antibody generation and human immunodeficiency virus inactivation.
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biochemical analysis of hypermutational targeting by wild type and mutant activation induced Cytidine Deaminase
Journal of Biological Chemistry, 2004Co-Authors: Ronda Bransteitter, Phuong Pham, Peter Calabrese, Myron F GoodmanAbstract:Abstract The synthesis of high affinity antibodies requires activation-induced Cytidine Deaminase (AID) to initiate somatic hypermutation and class-switch recombination. Here we investigate AID-catalyzed deamination of C → U on single-stranded DNA and on actively transcribed closed circular double-stranded DNA. Mutations are initially favored at canonical WRC (W = A or T, R = A or G) somatic hypermutation hot spot motifs, but over time mutations at neighboring non-hot spot sites increase creating random clusters of mutated regions in a seemingly processive manner. N-terminal AID mutants R35E and R35E/R36D appear less processive and have altered mutational specificity compared with wild type AID. In contrast, a C-terminal deletion mutant defective in CSR in vivo closely resembles wild type AID. A mutational spectrum generated during transcription of closed circular double-stranded DNA indicates that wild type AID retains its specificity for WRC hot spot motifs within the confines of a moving transcription bubble while introducing clusters of multiple deaminations predominantly on the nontranscribed strand.
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activation induced Cytidine Deaminase deaminates deoxyCytidine on single stranded dna but requires the action of rnase
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Ronda Bransteitter, Phuong Pham, Matthew D. Scharff, Myron F GoodmanAbstract:The expression of activation-induced Cytidine Deaminase (AID) is prerequisite to a “trifecta” of key molecular events in B cells: class-switch recombination and somatic hypermutation in humans and mice and gene conversion in chickens. Although this critically important enzyme shares common sequence motifs with apolipoprotein B mRNA-editing enzyme, and exhibits Deaminase activity on free deoxyCytidine in solution, it has not been shown to act on either RNA or DNA. Recent mutagenesis data in Escherichia coli suggest that AID may deaminate dC on DNA, but its putative biochemical activities on either DNA or RNA remained a mystery. Here, we show that AID catalyzes deamination of dC residues on single-stranded DNA in vitro but not on double-stranded DNA, RNA–DNA hybrids, or RNA. Remarkably, it has no measurable Deaminase activity on single-stranded DNA unless pretreated with RNase to remove inhibitory RNA bound to AID. AID catalyzes dC → dU deamination activity most avidly on double-stranded DNA substrates containing a small “transcription-like” single-stranded DNA bubble, suggesting a targeting mechanism for this enigmatic enzyme during somatic hypermutation.
Nasim A Begum - One of the best experts on this subject based on the ideXlab platform.
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nonimmunoglobulin target loci of activation induced Cytidine Deaminase aid share unique features with immunoglobulin genes
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Lucia Kato, Nasim A Begum, Maxwell A Burroughs, Tomomitsu Doi, Jun Kawai, Carsten O Daub, Takahisa Kawaguchi, Fumihiko Matsuda, Yoshihide HayashizakiAbstract:Activation-induced Cytidine Deaminase (AID) is required for both somatic hypermutation and class-switch recombination in activated B cells. AID is also known to target nonimmunoglobulin genes and introduce mutations or chromosomal translocations, eventually causing tumors. To identify as-yet-unknown AID targets, we screened early AID-induced DNA breaks by using two independent genome-wide approaches. Along with known AID targets, this screen identified a set of unique genes (SNHG3, MALAT1, BCL7A, and CUX1) and confirmed that these loci accumulated mutations as frequently as Ig locus after AID activation. Moreover, these genes share three important characteristics with the Ig gene: translocations in tumors, repetitive sequences, and the epigenetic modification of chromatin by H3K4 trimethylation in the vicinity of cleavage sites.
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discovery of activation induced Cytidine Deaminase the engraver of antibody memory
Advances in Immunology, 2007Co-Authors: Masamichi Muramatsu, Nasim A Begum, Hitoshi Nagaoka, Reiko Shinkura, Tasuku HonjoAbstract:Discovery of activation‐induced Cytidine Deaminase (AID) paved a new path to unite two genetic alterations induced by antigen stimulation; class switch recombination (CSR) and somatic hypermutation (SHM). AID is now established to cleave specific target DNA and to serve as engraver of these genetic alterations. AID of a 198‐residue protein has four important domains: nuclear localization signal and SHM‐specific region at the N‐terminus; the α‐helical segment (residue 47–54) responsible for dimerization; catalytic domain (residues 56–94) shared by all the other Cytidine Deaminase family members; and nuclear export signal overlapping with class switch‐specific domain at the C‐terminus. Two alternative models have been proposed for the mode of AID action; whether AID directly attacks DNA or indirectly through RNA editing. Lines of evidence supporting RNA editing hypothesis include homology in various aspects with APOBEC1, a bona fide RNA editing enzyme as well as requirement of de novo protein synthesis for DNA cleavage by AID in CSR and SHM. This chapter critically evaluates DNA deamination hypothesis and describes evidence to indicate UNG is involved not in DNA cleavage but in DNA repair of CSR. In addition, UNG appears to have a noncanonical function through interaction with an HIV Vpr‐like protein at the WXXF motif. Taken together, RNA editing hypothesis is gaining the ground.
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de novo protein synthesis is required for activation induced Cytidine Deaminase dependent dna cleavage in immunoglobulin class switch recombination
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Nasim A Begum, Kazuo Kinoshita, Masamichi Muramatsu, Hitoshi Nagaoka, Reiko Shinkura, Tasuku HonjoAbstract:Activation-induced Cytidine Deaminase is required for the DNA cleavage step of Ig class switch recombination (CSR). However, its molecular mechanism is controversial. RNA-editing hypothesis postulates that activation-induced Cytidine Deaminase deaminates cytosine in an unknown mRNA to generate a new mRNA encoding an endonuclease for CSR and thus predicts that DNA cleavage depends on de novo protein synthesis. On the other hand, DNA deamination hypothesis proposes that DNA cleavage is initiated by cytosine deamination in DNA, followed by uracil removal by uracil DNA glycosylase. By using the chromatin immunoprecipitation assay to detect γ-H2AX focus formation as a marker for DNA cleavage, we found that cycloheximide inhibited DNA cleavage in the Ig heavy-chain locus during CSR. Requirement of protein synthesis in the DNA cleavage step of CSR strengthens the RNA-editing hypothesis.
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activation induced Cytidine Deaminase shuttles between nucleus and cytoplasm like apolipoprotein b mrna editing catalytic polypeptide 1
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Hitoshi Nagaoka, Nasim A Begum, Masamichi Muramatsu, Reiko Shinkura, Mikiyo Nakata, Tasuku HonjoAbstract:Activation-induced Cytidine Deaminase (AID) is a molecule central to initiating class switch recombination, somatic hypermutation, and gene conversion of Ig genes. However, its mechanism to initiate these genetic alterations is still unclear. AID can convert cytosine to uracil on either mRNA or DNA and is involved in DNA cleavage. Although these events are expected to take place in the nucleus, overexpressed AID was found predominantly in the cytoplasm. Here, we demonstrated that AID is a nucleocytoplasmic shuttling protein with a bipartite nuclear localization signal and a nuclear export signal in its N and C termini, respectively. In addition to previously identified genetic, structural, and biochemical similarities of AID with apolipoprotein B mRNA editing catalytic polypeptide 1, an RNA editing enzyme of ApoB100 mRNA, the present finding provides another aspect to their resemblance, suggesting that both may have homologous reaction mechanisms.
