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Activation induced cytidine deaminase

Rachel A Woolaver, Xiaoguang Wang, Yonatan Dollin, Ping Xie, Jing H Wang, Zhangguo Chen
Effective humoral immunity requires class switch recombination (CSR) catalyzed by activation-induced cytidine deaminase (AID). In response to T cell-dependent (TD) Ags, CSR can be induced by CD40 signaling in B cells. TNFR-associated factors 2 and 3 (TRAF2/TRAF3) function as adaptors of the CD40 signaling pathway. B cell-intrinsic TRAF2 or TRAF3 (B-TRAF2 or B-TRAF3) knockout mice were previously reported to have indistinguishable phenotypes in gene expression, B cell survival and development, and enlarged peripheral lymphoid organs...
October 19, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Jeffrey R Atkinson, Mihyun Hwang, Angel Reyes-Rodriguez, Cornelia C Bergmann
Humoral responses within the central nervous system (CNS) are common to many neurotropic viral infections, with antibody (Ab) secreting cells (ASC) contributing to local protection. However, a role for virus-specific memory B cells (Bmem) within the CNS is poorly explored due to lack of robust phenotypic or functional identification in mice. This study takes advantage of mice expressing tamoxifen-inducible Cre recombinase (Cre-ERT2) under the Aicda promoter crossed with Rosa26-loxP-tdTomato reporter mice (AIDCre -Rosa26tdTomato ) to monitor B cells having undergone activation-induced cytidine deaminase (AID)-mediated somatic hypermutation (SHM) following neurotropic coronavirus infection...
October 17, 2018: Journal of Virology
Najwa El Kadi, Luo Wang, April Davis, Hasan Korkaya, Alexander Cooke, Varun Vadnala, Noah A Brown, Bryan L Betz, Marilia Cascalho, Gregory P Kalemkerian, Khaled A Hassan
Almost all patients with EGFR-driven lung cancer who are treated with EGFR tyrosine kinase inhibitors (TKI) develop resistance to treatment. A single base (c.2369C>T) transition mutation, EGFR T790M, is the most frequent resistance event after first-generation exposure to EGFR TKI. Whether T790M mutation is acquired or is selected from a pre-existing clone has been a matter of significant debate. In this study, we show that treatment with EGFR TKI leads to activation of the NFᴋB pathway, which in turn induces expression of Activation Induced Cytidine Deaminase (AICDA)...
October 17, 2018: Cancer Research
Verónica Delgado-Benito, Daniel B Rosen, Qiao Wang, Anna Gazumyan, Joy A Pai, Thiago Y Oliveira, Devakumar Sundaravinayagam, Wenzhu Zhang, Matteo Andreani, Lisa Keller, Kyong-Rim Kieffer-Kwon, Aleksandra Pękowska, Seolkyoung Jung, Madlen Driesner, Roman I Subbotin, Rafael Casellas, Brian T Chait, Michel C Nussenzweig, Michela Di Virgilio
Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3' Igh super-enhancer, 3' regulatory region (3'RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3'RR...
September 26, 2018: Molecular Cell
Juanjuan Yuan, Yunqing Ma, Tao Huang, Yanhao Chen, Yuanzheng Peng, Bing Li, Jia Li, Yuchen Zhang, Bing Song, Xiaofang Sun, Qiurong Ding, Yan Song, Xing Chang
RNA splicing is a critical mechanism by which to modify transcriptome, and its dysregulation is the underlying cause of many human diseases. It remains challenging, however, to genetically modulate a splicing event in its native context. Here, we demonstrate that a CRISPR-guided cytidine deaminase (i.e., targeted-AID mediated mutagenesis [TAM]) can efficiently modulate various forms of mRNA splicing. By converting invariant guanines to adenines at either 5' or 3' splice sites (SS), TAM induces exon skipping, activation of alternative SS, switching between mutually exclusive exons, or targeted intron retention...
October 18, 2018: Molecular Cell
Simar Pal Singh, Marjolein J W de Bruijn, Mariana P de Almeida, Ruud W J Meijers, Lars Nitschke, Anton W Langerak, Saravanan Y Pillai, Ralph Stadhouders, Rudi W Hendriks
Chronic lymphocytic leukemia (CLL) can be divided into prognostically distinct subsets with stereotyped or non-stereotyped, mutated or unmutated B cell receptors (BCRs). Individual subsets vary in antigen specificity and origin, but the impact of antigenic pressure on the CLL BCR repertoire remains unknown. Here, we employed IgH.TE μ mice that spontaneously develop CLL, expressing mostly unmutated BCRs of which ~35% harbor VH 11-2/Vκ14-126 and recognize phosphatidylcholine. Proportions of VH 11/Vκ14-expressing CLL were increased in the absence of functional germinal centers in IgH...
2018: Frontiers in Immunology
Yunxiang Mu, Kevin M McBride
The mutations induced by activation-induced cytidine deaminase (AID) trigger antibody diversification but can cause genome instability. We find that AID phosphorylation is an important determinant of "off-target" mutagenesis and identify a drug that increases this activity. These studies demonstrate how dysregulating AID phosphorylation can promote oncogenesis.
2018: Molecular & Cellular Oncology
Shengcai Yang, Dawei Zhang, Na Shen, Guanyi Wang, Zhaohui Tang, Xuesi Chen
Ovarian cancer is the major cause of death in women gynecological malignancy and gemcitabine (GEM) is commonly used in related chemotherapy. However, more than 90% GEM is catalyzed into an inactive metabolite 2'-deoxy-2',2'-difluorouridine by stromal and cellular cytidine deaminase (CDA). Dihydroartemisinin (DHA), which possesses an intramolecular endoperoxide bridge, could be activated by heme or ferrous iron to produce reactive oxygen species (ROS). The excess ROS generation will excite expression of heme oxygenase-1 and suppress CDA expression...
September 6, 2018: Journal of Cellular Biochemistry
Masayuki Kuraoka, Eric Meffre, Garnett Kelsoe
Activation-induced cytidine deaminase (AID) expression in the germinal center response drives the immunoglobulin class-switch recombination and V(D)J hypermutation necessary for efficacious, high-affinity antibody responses. That AID is expressed in developing lymphocytes is less well known, but represents an evolutionarily conserved pattern of lymphocyte development that is represented in all vertebrate species. Here we review the role of early, developmentally regulated AID expression in mice and humans and its role in establishing the first B-cell tolerance checkpoint...
2018: Advances in Immunology
David H Phillips
Reporter gene assays, in which a single mutation from each experiment can contribute to the assembly of a mutation spectrum for an agent, have provided the basis for understanding the mutational processes induced by mutagenic agents and for providing clues to the origins of mutations in human tumours. More recently exome and whole genome sequencing of human tumours has revealed distinct patterns of mutation that could provide additional clues for the causative origins of cancer. This can be tested by examining the mutational signatures induced in experimental systems by putative cancer-causing agents...
August 24, 2018: DNA Repair
Lindsay K Nicholson, Harsh Pratap, Elisabeth Bowers, Elise Gunzburger, Srinivasa R Bandi, Edward M Gardner, Brent E Palmer, Timothy Wright, John Kittelson, Edward N Janoff
Identifying HIV-1-associated B cell defects and responses to activation may direct interventions to circumvent their impaired antibody responses to infection and vaccines. Among 34 viremic HIV-1-infected and 20 seronegative control adults, we measured baseline frequencies and activation of B and T cell subsets, expression of activation-induced cytidine deaminase (AID), potential determinants of B cell activation in vivo and B and T cell responses in vitro. At baseline, HIV-1 infection was associated with increased IgM memory and decreased anergic cell frequencies, as well as increased activation in all 10 B cell subsets compared with controls...
September 7, 2018: Immunobiology
Peter M Bowers, William J Boyle, Robert Damoiseaux
The engineering of antibodies and antibody fragments for affinity maturation, stability, and other biophysical characteristics is a common aspect of therapeutic development. Maturation of antibodies in B cells during the adaptive immune response is the result of a process called somatic hypermutation (SHM), in which the activation-induced cytidine deaminase (AID) acts to introduce mutations into immunoglobulin (Ig) genes. Iterative selection and clonal expansion of B cells containing affinity-enhancing mutations drive an increase in the overall affinity of antibodies...
2018: Methods in Molecular Biology
John J Wilson, Kin-Hoe Chow, Nathan J Labrie, Jane A Branca, Thomas J Sproule, Bryant R A Perkins, Elise E Wolf, Mauro Costa, Grace Stafford, Christine Rosales, Kevin D Mills, Derry C Roopenian, Muneer G Hasham
Targeting the early steps of the glycolysis pathway in cancers is a well-established therapeutic strategy; however, the doses required to elicit a therapeutic effect on the cancer can be toxic to the patient. Consequently, numerous preclinical and clinical studies have combined glycolytic blockade with other therapies. However, most of these other therapies do not specifically target cancer cells, and thus adversely affect normal tissue. Here we first show that a diverse number of cancer models - spontaneous, patient-derived xenografted tumor samples, and xenografted human cancer cells - can be efficiently targeted by 2-deoxy-D-Glucose (2DG), a well-known glycolytic inhibitor...
September 5, 2018: Cancer Biology & Therapy
Hiroshi Nishimasu, Xi Shi, Soh Ishiguro, Linyi Gao, Seiichi Hirano, Sae Okazaki, Taichi Noda, Omar O Abudayyeh, Jonathan S Gootenberg, Hideto Mori, Seiya Oura, Benjamin Holmes, Mamoru Tanaka, Motoaki Seki, Hisato Hirano, Hiroyuki Aburatani, Ryuichiro Ishitani, Masahito Ikawa, Nozomu Yachie, Feng Zhang, Osamu Nureki
The RNA-guided endonuclease Cas9 cleaves its target DNA and is a powerful genome-editing tool. However, the widely used Streptococcus pyogenes Cas9 enzyme (SpCas9) requires an NGG protospacer adjacent motif (PAM) for target recognition, thereby restricting the targetable genomic loci. Here, we report a rationally engineered SpCas9 variant (SpCas9-NG) that can recognize relaxed NG PAMs. The crystal structure revealed that the loss of the base-specific interaction with the third nucleobase is compensated by newly introduced non-base-specific interactions, thereby enabling the NG PAM recognition...
September 21, 2018: Science
Juan Chen, Zhaokui Cai, Meizhu Bai, Xiaohua Yu, Chao Zhang, Changchang Cao, Xihao Hu, Lei Wang, Ruibao Su, Di Wang, Lei Wang, Yingpeng Yao, Rong Ye, Baidong Hou, Yang Yu, Shuyang Yu, Jinsong Li, Yuanchao Xue
Activation-induced cytidine deaminase (AID) mediates class switching by binding to a small fraction of single-stranded DNA (ssDNA) to diversify the antibody repertoire. The precise mechanism for highly selective AID targeting in the genome has remained elusive. Here, we report an RNA-binding protein, ROD1 (also known as PTBP3), that is both required and sufficient to define AID-binding sites genome-wide in activated B cells. ROD1 interacts with AID via an ultraconserved loop, which proves to be critical for the recruitment of AID to ssDNA using bi-directionally transcribed nascent RNAs as stepping stones...
October 2018: Cell Research
Chao-Yuan Tsai, Shuhei Sakakibara, Teruhito Yasui, Takeharu Minamitani, Daisuke Okuzaki, Hitoshi Kikutani
Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), which mimics a constitutively active receptor, is required for viral transformation of primary B cells. LMP1 is expressed in EBV-infected germinal center (GC) B cells of immunocompetent individuals, suggesting that it may contribute to persistent EBV infection. In this study, we generated and analyzed mice that expressed LMP1 under the control of the CD19 or activation-induced cytidine deaminase (AID) promoter. Expression of LMP1 induced activation of B cells but severely inhibited their differentiation into antibody-secreting cells (ASCs) in vitro and GC B cells in vivo...
August 21, 2018: International Immunology
Niccolò Bolli, Francesco Maura, Stephane Minvielle, Dominik Gloznik, Raphael Szalat, Anthony Fullam, Inigo Martincorena, Kevin J Dawson, Mehmet Kemal Samur, Jorge Zamora, Patrick Tarpey, Helen Davies, Mariateresa Fulciniti, Masood A Shammas, Yu Tzu Tai, Florence Magrangeas, Philippe Moreau, Paolo Corradini, Kenneth Anderson, Ludmil Alexandrov, David C Wedge, Herve Avet-Loiseau, Peter Campbell, Nikhil Munshi
We analyzed whole genomes of unique paired samples from smoldering multiple myeloma (SMM) patients progressing to multiple myeloma (MM). We report that the genomic landscape, including mutational profile and structural rearrangements at the smoldering stage is very similar to MM. Paired sample analysis shows two different patterns of progression: a "static progression model", where the subclonal architecture is retained as the disease progressed to MM suggesting that progression solely reflects the time needed to accumulate a sufficient disease burden; and a "spontaneous evolution model", where a change in the subclonal composition is observed...
August 22, 2018: Nature Communications
Maria Pia Cicalese, Jolanda Gerosa, Manuela Baronio, Davide Montin, Francesco Licciardi, Annarosa Soresina, Rosa Maria Dellepiane, Maurizio Miano, Lucia Augusta Baselli, Stefano Volpi, Carlo Dufour, Alessandro Plebani, Alessandro Aiuti, Vassilios Lougaris, Georgia Fousteri
Mutations in genes that control class switch recombination and somatic hypermutation during the germinal center (GC) response can cause diverse immune dysfunctions. In particular, mutations in CD40LG, CD40, AICDA , or UNG cause hyper-IgM (HIGM) syndrome, a heterogeneous group of primary immunodeficiencies. Follicular helper (Tfh) and follicular regulatory (Tfr) T cells play a key role in the formation and regulation of GCs, but their role in HIGM pathogenesis is still limited. Here, we found that compared to CD40 ligand (CD40L)- and activation-induced cytidine deaminase (AICDA)-deficient patients, circulating Tfh and Tfr cells were severely compromised in terms of frequency and activation phenotype in a child with CD40 deficiency...
2018: Frontiers in Immunology
Christine Grundström, Anjani Kumar, Anshu Priya, Neema Negi, Thomas Grundström
B lymphocytes optimize antibody responses by class switch recombination (CSR), which changes the expressed constant region exon of the immunoglobulin heavy chain (IgH), and by somatic hypermutation (SH) that introduces point mutations in the variable regions of the antibody genes. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates both these antibody diversification processes by deaminating cytosine to uracil. Here we asked the question if transcription factors can mediate the specific targeting of the antibody diversification by recruiting AID...
October 2018: European Journal of Immunology
Hyeseon Cho, Henrique Jaime, Rafael Pires de Oliveira, Byunghyun Kang, Rosanne Spolski, Tina Vaziri, Timothy G Myers, Vishal Thovarai, Zeli Shen, James G Fox, Warren J Leonard, Brian L Kelsall
Despite studies indicating the effects of IL-21 signaling in intestinal inflammation, its roles in intestinal homeostasis and infection are not yet clear. Here, we report potent effects of commensal microbiota on the phenotypic manifestations of IL-21 receptor deficiency. IL-21 is produced highly in the small intestine and appears to be critical for mounting an IgA response against atypical commensals such as segmented filamentous bacteria and Helicobacter, but not to the majority of commensals. In the presence of these atypical commensals, IL-21R-deficient mice exhibit reduced numbers of germinal center and IgA+ B cells and expression of activation-induced cytidine deaminase in Peyer's patches as well as a significant decrease in small intestine IgA+ plasmablasts and plasma cells, leading to higher bacterial burdens and subsequent expansion of Th17 and Treg cells...
August 7, 2018: Mucosal Immunology
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