The AID Dilemma

Honjo, Tasuku; Kobayashi, Maki; Begum, Noorzahan; Kotani, Ai; Sabouri, Somayeh; Nagaoka, Hitoshi

doi:10.1016/b978-0-12-394280-7.00001-4

Cited by 31 publications

(15 citation statements)

References 199 publications

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“…In comparison, SHM can be induced by CSR-deficient AID variants in cells (Hwang et al, 2015; Phamet al, 2016) and by APOBEC3 homologs during retroviral infection (Halemano et al, 2014), suggesting that mutations in Ig V regions may not require all the AID features employed in CSR. Because chromatin immunoprecipitation sequencing data showed that Ig V regions may not bind AID as stably as S regions (Matthews et al, 2014b), and the assistant patch mutant R174S also causes SHM deficiency (Durandy et al, 2006; Honjo et al, 2012), we speculate that Ig V regions may only transiently recruit AID using local secondary structures like branched DNA, which do not induce AID oligomerization and stable association.…”

Section: Discussionmentioning

confidence: 93%

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AID Recognizes Structured DNA for Class Switch Recombination

Qiao

Wang

Meng³

et al. 2017

Molecular Cell

151

194

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SUMMARY Activation-induced cytidine deaminase (AID) initiates both class switch recombination (CSR) and somatic hypermutation (SHM) in antibody diversification. Mechanisms of AID targeting and catalysis remain elusive despite its critical immunological roles and off-target effects in tumorigenesis. Here, we produced active human AID and revealed its preferred recognition and deamination of structured substrates. G-quadruplex (G4)-containing substrates mimicking the mammalian immunoglobulin switch regions are particularly good AID substrates in vitro. By solving crystal structures of maltose binding protein (MBP)-fused AID alone and in complex with deoxycytidine monophosphate, we surprisingly identify a bifurcated substrate-binding surface that explains structured substrate recognition by capturing two adjacent single-stranded overhangs simultaneously. Moreover, G4 substrates induce cooperative AID oligomerization. Structure-based mutations that disrupt bifurcated substrate recognition or oligomerization both compromise CSR in splenic B cells. Collectively, our data implicate intrinsic preference of AID for structured substrates and uncover the importance of G4 recognition and oligomerization of AID in CSR.

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Section: Discussionmentioning

confidence: 93%

“…Among the mutants, R174S was previously reported from patients with hyper-IgM syndrome (Durandy et al, 2006; Honjo et al, 2012; Table S3). Moreover, the AID-APOBEC3A hybrid AIDv (Pham et al, 2016) was also completely deficient in conducting CSR (Figures 5E and S1A), likely due to the disrupted substrate channel orientation (Figures 4F and S4F).…”

Section: Resultsmentioning

confidence: 99%

AID Recognizes Structured DNA for Class Switch Recombination

Qiao

Wang

Meng³

et al. 2017

Molecular Cell

151

194

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“…Cancer cells are considered to be generated from the stepwise accumulation of genetic alterations in various genes in inflammation-associated carcinogenesis (7). AID, a nucleotide-editing enzyme that is essential for somatic hypermutation and class-switch recombination of the immunoglobulin gene, is also known to serve a role as a genomic mutator in carcinogenesis (9). Shimizu et al (7) demonstrated that pathogenic bacterial or viral factors and subsequent inflammatory reactions in H. pylori -related gastritis, chronic viral hepatitis, Barrett's esophagus and inflammatory bowel disease lead to the aberrant expression of AID in various epithelial cells via NF-κB activation, which causes the accumulation of genetic alterations in tumor-related genes.…”

Section: Discussionmentioning

confidence: 99%

“…PAX5, known as a B cell-specific activator protein, serves a role as an activator for AID (9). In the present study, the aberrant expression of PAX5 and AID was more frequently observed in EBV-non-associated GC compared with in EBVaGC (P=0.01 and P=0.025, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…Honjo et al (9) described pathogen-induced AID expression in gastric cancer (caused by H. pylori ), adult T cell leukemia/lymphoma (caused by human T lymphotrophic virus 1), hepatoma (caused by hepatitis C virus) and Burkitt's lymphoma (caused by EBV), but not in classical Hodgkin's lymphoma (caused by EBV) (9). However, to the best of our knowledge, aberrant AID expression in EBVaGC has not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Aberrant expression of AID and AID activators of NF-κB and PAX5 is irrelevant to EBV-associated gastric cancers, but is associated with carcinogenesis in certain EBV-non-associated gastric cancers

et al. 2017

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Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype of gastric cancer characterized by clinicopathological features including lymphoepithelioma-like histology. Aberrant expression of activation-induced cytidine deaminase (AID) as a genomic modulator was demonstrated through pathogen-related nuclear factor κB (NF-κB) signaling in Helicobacter pylori-associated gastric cancer. To elucidate whether or not AID expression is relevant to carcinogenesis in EBVaGC, immunohistochemical expression of AID and AID-regulatory factors between EBVaGC and EBV-non-associated gastric carcinoma (GC) were evaluated, each using 15 cases of GC with lymphoid stroma (GCLS) and other types of GC. Aberrant expression of AID, NF-κB and paired box 5 (PAX5) were significantly decreased in EBVaGC (0/11, 1/11 and 1/11) compared with in EBV-non-associated GC (7/19, 12/19 and 11/19) (P=0.025, 0.005 and 0.01, respectively); however, no significant difference in c-Myb proto-oncogene expression was identified. AID expression was also decreased in EBV-associated GCLS (0/10) compared with in EBV-non-associated GCLS (3/5). Unexpectedly, decreased expression of NF-κB and PAX5 was observed in GCLS (1/15 and 2/15) compared with in GC without LS (12/15 and 10/15) (P<0.001 and P=0.003, respectively). Decreased AID expression observed in EBVaGC is consistent with the reported molecular characterization of hypermethylation and rare somatic gene mutation in EBVaGC. Only PAX5 was identified to be significantly associated with venous invasion (P=0.022). The results of the present study suggest that pathogen-induced AID expression may be irrelevant to carcinogenesis of EBVaGC, whereas it contributes to carcinogenesis in certain types of EBV-non-associated GC.

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TGF‐β triggers HBV cccDNA degradation through AID‐dependent deamination

et al. 2016

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The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a viral center molecule for HBV infection and persistence. However, the cellular restriction factors of HBV cccDNA are not well understood. Here, we show that TGF-b can induce nuclear viral cccDNA degradation and hypermutation via activation-induced cytidine deaminase (AID) deamination activity in hepatocytes. This suppression by TGF-b is abrogated when AID or the activity of uracil-DNA glycosylase (UNG) is absent, which indicates that AID deamination and the UNG-mediated excision of uracil act in concert to degrade viral cccDNA. Moreover, the HBV core protein promotes the interaction between AID and viral cccDNA. Overall, our results indicate a novel molecular mechanism that allows cytokine TGF-b to restrict viral nuclear cccDNA in innate immunity, thereby suggesting a novel method for potentially eliminating cccDNA.Keywords: AID; cccDNA; HBV; Hypermutation; UNG Highlights • AID triggers HBV cccDNA degradation via its deamination activity.• AID induces viral cccDNA hypermutation.• TGF-b reduces viral cccDNA through AID in hepatocytes.Almost 350 million people who are chronically infected with hepatitis B virus (HBV) worldwide are at high risk of developing liver cirrhosis and hepatocellular carcinoma. Thus, HBV infection is a major global health concern [1-3]. The covalently closed circular DNA (cccDNA) of HBV plays an essential role in virus replication and persistence. After entry into the hepatocytes, HBV first forms cccDNA in the host cell's nucleus before transcribing viral RNAs, including a replicative RNA intermediate called pregenomic (pg) RNA that encodes two viral proteins, HBV core (HBc), and HBV polymerase (Pol), which encapsidate pgRNA to form a nucleocapsid. HBV Pol reverse transcribes pgRNA to produce relaxed circular DNA

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The AID Dilemma

Cited by 31 publications

References 199 publications

AID Recognizes Structured DNA for Class Switch Recombination

AID Recognizes Structured DNA for Class Switch Recombination

Aberrant expression of AID and AID activators of NF-κB and PAX5 is irrelevant to EBV-associated gastric cancers, but is associated with carcinogenesis in certain EBV-non-associated gastric cancers

TGF‐β triggers HBV cccDNA degradation through AID‐dependent deamination

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