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Activation induced cytidine deaminase AID

Fernando Grigera, Robert Wuerffel, Amy L Kenter
Immunoglobulin heavy chain class switch recombination (CSR) requires targeted formation of DNA double strand breaks (DSBs) in repetitive switch region elements followed by ligation between distal breaks. The introduction of DSBs is initiated by activation induced cytidine deaminase (AID) and requires base excision repair (BER) and mismatch repair (MMR). The BER enzyme, methyl CpG binding domain protein 4 (MBD4) has been linked to the MMR pathway through its interaction with MutL homologue 1 (MLH1). We find that when the Mbd4 exons 6-8 are deleted in a switching B cell line DSB formation is severely reduced and CSR frequency is impaired...
October 24, 2016: Molecular and Cellular Biology
Yunqing Ma, Jiayuan Zhang, Weijie Yin, Zhenchao Zhang, Yan Song, Xing Chang
A large number of genetic variants have been associated with human diseases. However, the lack of a genetic diversification approach has impeded our ability to interrogate functions of genetic variants in mammalian cells. Current screening methods can only be used to disrupt a gene or alter its expression. Here we report the fusion of activation-induced cytidine deaminase (AID) with nuclease-inactive clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (dCas9) for efficient genetic diversification, which enabled high-throughput screening of functional variants...
October 10, 2016: Nature Methods
Ravendra Garg, Michael Theaker, Elisa C Martinez, Sylvia van Drunen Littel-van den Hurk
Respiratory syncytial virus (RSV) causes serious respiratory illness in infants and elderly. RSV infection induces short-lived immunity, which leaves people prone to re-infection. In contrast, the RSV fusion (F) protein formulated with a novel adjuvant (∆F/TriAdj) elicits long term protective immunity. A comparison of RSV-immunized mice to mice vaccinated with a single dose of ∆F/TriAdj showed no difference in IgG1 and IgG2a production; however, local IgA secreting memory B cell development and B cell IgA production were significantly lower in RSV vaccinated mice than in ∆F/TriAdj-immunized mice...
October 6, 2016: Virology
Hanen Ouadani, Imen Ben-Mustapha, Meriem Ben-Ali, Beya Larguèche, Tihana Jovanic, Sylvie Garcia, Benoit Arcangioli, Houda Elloumi-Zghal, Dahmani Fathallah, Mongia Hachicha, Hatem Masmoudi, François Rougeon, Mohamed-Ridha Barbouche
Activation induced cytidine deaminase (AID) is an essential enzyme for class switch recombination (CSR) and somatic hypermutation (SHM) during secondary immune response. Mutations in the AICDA gene are responsible for Hyper IgM 2 syndrome where both CSR and SHM or only CSR are affected. Indeed, triggering either of the two mechanisms requires the DNA deamination activity of AID. Besides, different domains of AID may be differentially involved in CSR and SHM through their interaction with specific cofactors...
October 4, 2016: Molecular Immunology
Tineke Cantaert, Jean-Nicolas Schickel, Jason M Bannock, Yen-Shing Ng, Christopher Massad, Fabien R Delmotte, Natsuko Yamakawa, Salome Glauzy, Nicolas Chamberlain, Tuure Kinnunen, Laurence Menard, Aubert Lavoie, Jolan E Walter, Luigi D Notarangelo, Julie Bruneau, Waleed Al-Herz, Sara Sebnem Kilic, Hans D Ochs, Charlotte Cunningham-Rundles, Mirjam van der Burg, Taco W Kuijpers, Sven Kracker, Hideo Kaneko, Yujin Sekinaka, Shigeaki Nonoyama, Anne Durandy, Eric Meffre
Patients with mutations in AICDA, which encodes activation-induced cytidine deaminase (AID), display an impaired peripheral B cell tolerance. AID mediates class-switch recombination (CSR) and somatic hypermutation (SHM) in B cells, but the mechanism by which AID prevents the accumulation of autoreactive B cells in blood is unclear. Here, we analyzed B cell tolerance in AID-deficient patients, patients with autosomal dominant AID mutations (AD-AID), asymptomatic AICDA heterozygotes (AID+/-), and patients with uracil N-glycosylase (UNG) deficiency, which impairs CSR but not SHM...
October 4, 2016: Journal of Clinical Investigation
Ann M Moormann, Jeffrey A Bailey
Burkitt lymphoma (BL) is >90% EBV-associated when this pediatric cancer is diagnosed in regions heavily burden by endemic Plasmodium falciparum malaria and thus has been geographically classified as endemic BL. The incidence of endemic BL is 10-fold higher compared to BL diagnosed in non-malarious regions of the world. The other forms of BL have been classified as sporadic BL which contain EBV in ∼30% of cases and immunodeficiency BL which occurs in HIV-infected adults with ∼40% of tumors containing EBV...
September 26, 2016: Current Opinion in Virology
S Kasar, J R Brown
Sequencing studies have been instrumental in understanding the genetic basis of chronic lymphocytic leukemia (CLL). Our recent whole-genome sequencing study focusing on lower cytogenetic risk CLL demonstrated that CLL mutations can be attributed to 3 key mutational processes-2 types of activation induced-cytidine deaminase (AID) signatures and an aging signature-that operate at different times throughout CLL evolution.
July 2016: Molecular & Cellular Oncology
Song-Yi Moon, Hye-Ju Eun, Sang-Ki Baek, Sang-Jin Jin, Tae-Suk Kim, Sung-Woo Kim, Hwan-Hoo Seong, In-Chul Choi, Joon-Hee Lee
Activation-induced cytidine deaminase (AID) is the only enzyme that has been suggested as a putative DNA demethylase in mammals. However, very little is known about AID function as DNA demethylase of bovine differentiated cells toward pluripotent state. To investigate the effect of AID on DNA demethylation, bovine AID complementary DNAs were transfected into bovine differentiated cells, which were mostly methylated in the promoter regions of pluripotency genes. As a result, AID-transfected bovine cells started to transform into colonies at day 19 of transfection...
October 2016: Cellular Reprogramming
Xudong Ao, Rula Sa, Jie Wang, Rinuo Dao, Huimin Wang, Haiquan Yu
DNA methylation in mammals is an epigenetic marker and necessary for normal embryogenesis. The global genomic demethylation of 5-methylcytosine occurs during the first cell cycle following fertilization. Activation-induced cytidine deaminase (AID), which is well-known for the function in antibody diversification, has been implicated to play a role in active demethylation, but its role in cell reprogramming and its crosstalk with other DNA demethylation mechanism need to be clarified. In this study, the dynamic epigenetic regulation of cell pluripotency and embryo development by AID in bovine preimplantation embryos was investigated...
August 9, 2016: Cytotechnology
Keiji Nishida, Takayuki Arazoe, Nozomu Yachie, Satomi Banno, Mika Kakimoto, Mayura Tabata, Masao Mochizuki, Aya Miyabe, Michihiro Araki, Kiyotaka Y Hara, Zenpei Shimatani, Akihiko Kondo
The generation of genetic variation (somatic hypermutation) is an essential process for the adaptive immune system in vertebrates. We demonstrate the targeted single-nucleotide substitution of DNA using hybrid vertebrate and bacterial immune systems components. Nuclease-deficient type II CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated) and the activation-induced cytidine deaminase (AID) ortholog PmCDA1 were engineered to form a synthetic complex (Target-AID) that performs highly efficient target-specific mutagenesis...
September 16, 2016: Science
Robyn A Lindley, Patrick Humbert, Cliff Larner, Eric H Akmeemana, Christopher R R Pendlebury
Evidence already exists that the activation-induced cytidine deaminase (AID/APOBEC) and the adenosine deaminase (ADAR) families of enzymes are implicated as powerful mutagens in oncogenic processes in many somatic tissues. Each deaminase is identified by the DNA or RNA nucleotide sequence ("motif") surrounding the nucleotide targeted for deamination. The primary objective of this study is to develop an in silico approach to identify nucleotide sequence changes of the target motifs of key deaminases during oncogenesis...
September 2016: Cancer Medicine
Daan J Aan de Kerk, Machiel H Jansen, Stephen Jolles, Klaus Warnatz, Suranjith L Seneviratne, Ineke J M Ten Berge, Ester M M van Leeuwen, Taco W Kuijpers
Primary antibody deficiencies (PADs) are the most common immunodeficiency in humans, characterized by low levels of immunoglobulins and inadequate antibody responses upon immunization. These PADs may result from an early block in B cell development with a complete absence of peripheral B cells and lack of immunoglobulins. In the presence of circulating B cells, some PADs are genetically caused by a class switch recombination (CSR) defect, but in the most common PAD, common variable immunodeficiency (CVID), very few gene defects have as yet been characterized despite various phenotypic classifications...
October 2016: Journal of Clinical Immunology
Edward J Steele
For 30 years two general mechanisms have competed to explain somatic hypermutation of immunoglobulin (Ig) genes. The first, the DNA-based model, is focused only on DNA substrates. The modern form is the Neuberger "DNA Deamination Model" based on activation-induced cytidine deaminase (AID) and short-patch error-prone DNA repair by DNA Polymerase-η operating around AID C-to-U lesions. The other is an RNA-based mechanism or the "Reverse Transcriptase Model" of SHM which produces strand-biased mutations at A:T and G:C base pairs...
September 2016: DNA Repair
Louise Saul, Kristina M Ilieva, Heather J Bax, Panagiotis Karagiannis, Isabel Correa, Irene Rodriguez-Hernandez, Debra H Josephs, Isabella Tosi, Isioma U Egbuniwe, Sara Lombardi, Silvia Crescioli, Carl Hobbs, Federica Villanova, Anthony Cheung, Jenny L C Geh, Ciaran Healy, Mark Harries, Victoria Sanz-Moreno, David J Fear, James F Spicer, Katie E Lacy, Frank O Nestle, Sophia N Karagiannis
B cells participate in immune surveillance in human circulation and tissues, including tumors such as melanoma. By contrast, the role of humoral responses in cutaneous immunity is underappreciated. We report circulating skin-homing CD22+CLA+B cells in healthy volunteers and melanoma patients (n = 73) and CD22+ cells in melanoma and normal skin samples (n = 189). Normal and malignant skin featured mature IgG and CD22 mRNA, alongside mRNA for the transiently-expressed enzyme Activation-induced cytidine Deaminase (AID)...
2016: Scientific Reports
Seiya Yokoyama, Michiyo Higashi, Sho Kitamoto, Monika Oeldorf, Uwe Knippschild, Marko Kornmann, Kosei Maemura, Hiroshi Kurahara, Edwin Wiest, Tomofumi Hamada, Ikumi Kitazono, Yuko Goto, Takashi Tasaki, Tsubasa Hiraki, Kazuhito Hatanaka, Yuko Mataki, Hiroki Taguchi, Shinichi Hashimoto, Surinder K Batra, Akihide Tanimoto, Suguru Yonezawa, Michael A Hollingsworth
Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method...
June 8, 2016: Oncotarget
Caitlin Bohannon, Ryan Powers, Lakshmipriyadarshini Satyabhama, Ang Cui, Christopher Tipton, Miri Michaeli, Ioanna Skountzou, Robert S Mittler, Steven H Kleinstein, Ramit Mehr, Francis Eun-Yun Lee, Ignacio Sanz, Joshy Jacob
Long-lived plasma cells are critical to humoral immunity as a lifelong source of protective antibodies. Antigen-activated B cells-with T-cell help-undergo affinity maturation within germinal centres and persist as long-lived IgG plasma cells in the bone marrow. Here we show that antigen-specific, induced IgM plasma cells also persist for a lifetime. Unlike long-lived IgG plasma cells, which develop in germinal centres and then home to the bone marrow, IgM plasma cells are primarily retained within the spleen and can develop even in the absence of germinal centres...
June 7, 2016: Nature Communications
Yuji Eso, Atsushi Takai, Tomonori Matsumoto, Tadashi Inuzuka, Takahiro Horie, Koh Ono, Shinji Uemoto, Kyeryoung Lee, Winfried Edelmann, Tsutomu Chiba, Hiroyuki Marusawa
Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFα stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-κB-dependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2(-) (/) (-)AID(+), ALB-MSH2(-) (/) (-), and ALB-AID(+) mice, in which MSH2 is deficient and/or activation-induced cytidine deaminase (AICDA) is expressed in cells with albumin-producing hepatocytes...
August 1, 2016: Cancer Research
Marina Romanello, Davide Schiavone, Alexander Frey, Julian E Sale
Immunoglobulin diversification is driven by activation-induced deaminase (AID), which converts cytidine to uracil within the Ig variable (IgV) regions. Central to the recruitment of AID to the IgV genes are factors that regulate the generation of single-stranded DNA (ssDNA), the enzymatic substrate of AID Here, we report that chicken DT40 cells lacking variant histone H3.3 exhibit reduced IgV sequence diversification. We show that this results from impairment of the ability of AID to access the IgV genes due to reduced formation of ssDNA during IgV transcription...
July 1, 2016: EMBO Journal
Jens S Kalchschmidt, Rachael Bashford-Rogers, Kostas Paschos, Adam C T Gillman, Christine T Styles, Paul Kellam, Martin J Allday
Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma. Using various Epstein-Barr virus (EBV) recombinants, we provide definitive evidence that the viral nuclear protein EBNA3C is essential in EBV-infected primary B cells for the induction of AID mRNA and protein. Using lymphoblastoid cell lines (LCLs) established with EBV recombinants conditional for EBNA3C function, this was confirmed, and it was shown that transactivation of the AID gene (AICDA) is associated with EBNA3C binding to highly conserved regulatory elements located proximal to and upstream of the AICDA transcription start site...
May 30, 2016: Journal of Experimental Medicine
Hongxue Meng, Huining Li, Rintaro Ohe, Ye Aung Naing, Suran Yang, Takanobu Kabasawa, Tomoya Kato, Mitsumasa Osakabe, Hiroya Ohtake, Akihiro Ishida, Junli Lu, Lei Zhang, Nobuo Ohta, Seiji Kakehata, Kensuke Joh, Qingtao Shi, Xiaoming Jin, Jingshu Geng, Mitsunori Yamakawa
Immunoglobulin A (IgA) nephropathy (IgAN) is characterized by high serum IgA levels and IgA deposition in the renal mesangium. Previous studies suggest that elevated serum IgA partly originates from the tonsils. Here, we investigated the mechanisms of IgA production in the tonsils of patients with IgAN. Immunohistochemistry revealed that the number and relative percentage of IgA-bearing cells were significantly increased in the tonsils of IgAN patients. Compared with non-IgAN patients, enhanced IgA class switching and overexpression of thymic stromal lymphopoietin (TSLP), TSLP receptor (TSLPR), activation-induced cytidine deaminase (AID), transforming growth factor-β1 (TGF-β1), B cell-activating factor of the tumor necrosis factor family (BAFF), and a proliferation-inducing ligand (APRIL) were detected in follicular dendritic cells (FDCs) of tonsillar germinal centers from IgAN patients...
October 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
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