It is one of several deaminases responsible for maintaining the cellular pyrimidine pool. Jan 30, 2002 activation induced cytidine deaminase aid, which is expressed specifically in germinalcentre centroblasts 1, is required for this process, but its exact role is unknown 2. Omim entry 605257 activationinduced cytidine deaminase. Activationinduced cytidine deaminase links ovulationinduced inflammation and serous carcinogenesis. B cell rab7 mediates induction of activationinduced. Class switch recombination and hypermutation require activation induced cytidine deaminase aid, a potential rna editing enzyme previous article ring finger proteins next article activation induced cytidine deaminase aid deficiency causes the autosomal recessive form of the hyperigm syndrome higm2. Activation induced cytidine deaminase aid, a nucleotideediting enzyme that triggers dna alterations and doublestrand dna breaks in the immunoglobulin gene, has been identified in activated b lymphocytes. Activationinduced cytidine deaminase in chronic lymphocytic. Activationinduced cytidine deaminase aid is localized. This gene encodes a rnaediting deaminase that is a member of the cytidine deaminase family. Based on homology, it was originally proposed to be an rnaediting enzyme, but so far, no rna substrates are known. Recent studies revealed that aidmediated genotoxic effects target not only immunoglobulin genes but also a variety of other genes in both. Activationinduced cytidine deaminase, also known as aicda and aid, is a 24 kda enzyme which in humans is encoded by the aicda gene. Activationinduced cytidine deaminase does not impact murine meiotic recombination catarina s.
Activationinduced cytidine deaminase expression in t. The enzymes cytidine deaminase domain introduces uracil residues into the dna of s and v. Potential roles of activationinduced cytidine deaminase. Activationinduced cytidine deaminase aid initiates antibody gene diversification by creating u. We previously discovered activationinduced cytidine deaminase aid, which induces both point mutations and recombination in ig genes and diversifies the ab repertoire in b lymphocytes. Using chromosomally integrated fluorescence reporter transgenes, we demonstrate a new recombinogenic activity of aid leading to intra and intergenic. Jci involvement of activationinduced cytidine deaminase in. Activationinduced cytidine deaminase aid has been shown to be essential for shm, gene conversion, and class switch recombination csr, three types of genetic alteration induced by antigen stimulation of b lymphocytes 59. Activationinduced cytidine deaminase aid can target both dna. Activationinduced cytidine deaminase targets dna at. B cell activation, as well as infection with andor exposure to several oncogenic viruses ebv, hepatitis c virus, hiv, leads to the induction of a cytidine deaminase necessary for igh class switch recombination csr and somatic hypermutation shm. Moreover, epsteinbarr virus ebv latent membrane protein1 lmp1 increases. Activationinduced cytidine deaminase aid, produced by the aicda gene, is essential for the immunoglobulin gene ig alterations that form immune memory. Activationinduced cytidine deaminase aid, which is expressed specifically in germinalcentre centroblasts 1, is required for this process, but its exact role is unknown 2.
This facilitates development of ig diversity and specificity for the recognition of intruding pathogens through humoral immunity governed by b cells 11 14. The activation induced cytidine deaminase aid is required for somatic. Both somatic mutation and class switching require an enzyme called activation induced cytidine deaminase aid that converts deoxycytidines to deoxyuracils. Potential roles of activationinduced cytidine deaminase in promotion or prevention of autoimmunity in humans anne durandy, 1, 2, 3 tineke cantaert, 4 sven kracker, 1, 2 and eric meffre 4 1 inserm, unite u768, hopital necker enfantsmalades, paris, france. To evaluate the impact of affinity maturation and isotype switching, we have interrogated the effect of aiddeficiency in an animal model of ms. Moreover, epsteinbarr virus ebv latent membrane protein1 lmp. Songa, prabha tiwaria, hiroki itoa, yuki yamaguchib, kazuyuki yoshizakia,c. Cytidine deaminase an overview sciencedirect topics. Apr 28, 2020 this gene encodes a rnaediting deaminase that is a member of the cytidine deaminase family. Jul 25, 2004 activation induced cytidine deaminase aid is a singlestranded ss dna deaminase required for somatic hypermutation shm and class switch recombination of immunoglobulin genes. Activationinduced cytidine deaminase aided in vitro.
Activationinduced cytidine deaminase exhibits a processive behavior in vitro when catalyzing deaminations, much like that of rna and dna polymerases, in that it preferentially mutates dc on the same dna strand 59, but its behavior is more like that of restriction enzymes in that it tends to slide and jump along that strand 107. The protein is involved in somatic hypermutation, gene conversion, and classswitch recombination of immunoglobulin genes. Role of activationinduced cytidine deaminase in inflammation. Expression of activationinduced cytidine deaminase aid is crucial for immunoglobulin v gene somatic hypermutations shms and immunoglobulin class switch recombinations csrs. Anne durandy, sven kracker, in stiehms immune deficiencies, 2014. We previously discovered activation induced cytidine deaminase aid, which induces both point mutations and recombination in ig genes and diversifies the ab repertoire in b lymphocytes. Elevated expression of activation induced cytidine. Recent research has shown that activationinduced cytidine deaminase aid triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Activationinduced cytidine deaminase links ovulation.
Induction of homologous recombination between sequence. Such aberrant aid expression is seen in bcell leukemialymphomas, including burkitt lymphoma which is associated with cmyc translocation. We investigated whether aid induces genetic aberrations at specific chromosomal loci that encode tumorrelated proteins in gastric epithelial. Humans with aid mutations develop not only the autosomal recessive form of hyperigm syndrome higm2 associated with b cell hyperplasia, but also autoimmune disorders by unknown mechanisms. Aid is related to apobec1, a known cytidine deaminase that acts on a specific rna for apolipoprotein b, converting a c residue to a u resulting in a premature stop codon. Defects in this gene are the cause of autosomal recessive hyperigm immunodeficiency syndrome type 2 higm2. Catalytic pocket inaccessibility of activationinduced cytidine deaminase is a safeguard against excessive mutagenic activity justin j. These processes take place within germinal centers of secondary lymphoid organs. Among pure b cell defects, the activationinduced cytidine deaminase aiddeficiency, characterized by a complete lack of immunoglobulin class switch recombination and somatic hypermutation, is especially complicated by. Both class switch recombination csr and somatic hypermutation shm are dependent on the action of activationinduced cytidine deaminase aid. Pdf activationinduced cytidine deaminase aid linking immunity. Activationinduced cytidine deaminase aid linking immunity. Aid deficiency caused a complete defect in class switching and showed a hyperigm phenotype with enlarged germinal centers containing strongly activated b cells before or after immunization. Like somatic hypermutation, csr requires activationinduced cytidine deaminase aid, whose expression is restricted to b cells, as induced by cd40 engagement or dual tlrbcr engagement primary csrinducing stimuli.
Jci involvement of activationinduced cytidine deaminase. Activationinduced cytidine deaminase links ovulationinduced. A protein antagonist of activationinduced cytidine deaminase. Activationinduced cytidine deaminase in b cell immunity. Activationinduced cytidine deaminase expression in t cells. Potential roles of activationinduced cytidine deaminase in. Dynamics of activationinduced cytidine deaminase expression. Regulation of hypermutation by activationinduced cytidine. Apr 01, 2005 expression of activation induced cytidine deaminase aid is crucial for immunoglobulin v gene somatic hypermutations shms and immunoglobulin class switch recombinations csrs. Original studies on human lymphomas indicated that aid is expressed in b cell lymphomas of germinal center gc origin.
The encoded protein forms a homotetramer that catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine, respectively. B cell activation and differentiation rutgers new jersey. Activation induced cytidine deaminase in b cell immunity and cancers seokrae park department of microbiology, college of medicine, konyang university, daejeon 302718, korea activation induced cytidine deaminase aid is an enzyme that is predominantly expressed in germinal center b cells and plays a pivotal role in immunoglobulin class. Activationinduced cytidine deaminase turns on somatic. Directed evolution of activationinduced cytidine deaminase. Activationinduced cytidine deaminase in b cell immunity and.
Activationinduced cytidine deaminase aid initiates somatic hypermutation shm by converting deoxycytidines dc to deoxyuracils du which then can induce other mutations, and plays a central role in introducing diversification of the antibody repertoire in b cells. Activationinduced cytidine deaminase aid initiates ig class switch recombination. Activationinduced cytidine deaminase in b cell immunity and cancers seokrae park department of microbiology, college of medicine, konyang university, daejeon 302718, korea activationinduced cytidine deaminase aid is an enzyme that is predominantly expressed in germinal center b cells and plays a pivotal role in immunoglobulin class. Activationinduced cytidine deaminase aided in vitro antibody. The encoded protein forms a homotetramer that catalyzes the. Activationinduced cytidine deaminase aidassociated. Catalytic pocket inaccessibility of activationinduced. Activation induced cytidine deaminase aid initiates antibody gene diversification by creating u. Nov 01, 2003 both class switch recombination csr and somatic hypermutation shm are dependent on the action of activation induced cytidine deaminase aid. Overexpression of activationinduced cytidine deaminase in. Activationinduced cytidine deaminase aid expressed by germinal center b cells is a central regulator of somatic hypermutation shm and class switch recombination csr.
We investigated whether aid induces genetic aberrations at specific chromosomal loci that. Cytidine deaminase is an enzyme that in humans is encoded by the cda gene. Critical role of activation induced cytidine deaminase in. Activation induced cytidine deaminase aid not only promotes immune diversity by initiating somatic hypermutation and class switch recombination in immunoglobulin genes but also provokes genomic instability by introducing translocations and mutations into nonimmunoglobulin genes. Activationinduced cytidine deaminase deficiency causes organ. A protein antagonist of activationinduced cytidine deaminase encoded by a complex mouse.
Activationinduced cytidine deaminase does not impact. Activationinduced cytidine deaminase aid is responsible for the induction of three reactions of dna somatic modification employed by jawed vertebrates in the context of adaptive immunity. Activationinduced cytidine deaminase aid, a member of a cytidine deaminase family, and apobec3b induce somatic mutations and recently have been indicated to be involved in the pathomechanism of. Jul 08, 2014 the activation induced cytidine deaminase aid protein is known to initiate somatic hypermutation, gene conversion or switch recombination by cytidine deamination within the immunoglobulin loci. Both class switch recombination csr and somatic hypermutation shm are dependent on the action of activation induced cytidine deaminase aid. The role of activationinduced cytidine deaminase in antibody. Activationinduced cytidine deaminase autoactivates and triggers aberrant gene expression tomoyasu isobea,b, sokennakazawa j. Aid and a1 induced ctou mutations in the viral rna of rnase hdefective hbv. Class switch dna recombination csr is central to the maturation of the ab response because it diversifies ab effector functions. Upregulation of activationinduced cytidine deaminase. Barrett,1 susanne raber,1 heather lucas,1 patricia sutter,1 and mani larijani1. The activation induced cytidine deaminase aid protein is known to initiate somatic hypermutation, gene conversion or switch recombination by cytidine deamination within the immunoglobulin loci. In mice, aid overexpression caused spontaneous tumors in. Activationinduced cytidine deaminase autoactivates and.
We performed an shrna screen to identify factors required for. Activationinduced cytidine deaminase aid, an important enzyme for b cell function, is responsible for the initiation of the somatic hypermutation and classswitch recombination. Autoimmune manifestations are paradoxical and frequent complications of primary immunodeficiencies, including t andor b cell defects. Activation induced cytidine deaminase is a key 198 aminoacid protein. Under normal conditions, it is only expressed in activated b cells i. Activation induced cytidine deaminase aid initiates somatic hypermutation shm by converting deoxycytidines dc to deoxyuracils du which then can induce other mutations, and plays a central role in introducing diversification of the antibody repertoire in b cells. Helicobacter pylori infection of gastric epithelial cells leads to aberrant expression of aid and somatic gene mutations. Activationinduced cytidine deaminase deaminates deoxycytidine on singlestranded dna but requires the action of rnase ronda bransteitter, phuong pham, matthew d. Krokan, bodil kavlin central norway health authorities and department of cancer research and molecular medicine, faculty of medicine, ntnu, n7491. Somatic hypermutation shm, class switch recombination csr and immunoglobulin gene conversion ig gc. Induced overexpression of aid in ch12f32 b lymphoma cells augmented class switching from igm to iga without cytokine stimulation.
Activationinduced cytidine deaminase is dispensable for. Activationinduced cytidine deaminase aid is localized to. Activation induced cytidine deaminase aid expressed by germinal center b cells is a central regulator of somatic hypermutation shm and class switch recombination csr. Activationinduced cytidine deaminase is a key 198 aminoacid protein. In mice, aid overexpression caused spontaneous tumors in various organs with mutations in nonig genes 3, 4. Activationinduced cytidine deaminase aid not only promotes immune diversity by initiating somatic hypermutation and class switch recombination in immunoglobulin genes but also provokes genomic instability by introducing translocations and mutations into nonimmunoglobulin genes. Here, we have proposed that activation induced cytidine deaminase aid, encoded by aicda links chronic inflammation and skin cancer. Activationinduced cytidine deaminase aid is an essential regulator of b cell diversification, but its full range of action has until recently been an enigma. Activationinduced cytidine deaminase aid is expressed in b cells within germinal.
The information on this page was automatically extracted from online scientific databases. Elevated expression of activation induced cytidine deaminase. Recent research has shown that activation induced cytidine deaminase aid triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Although it was initially envisaged that aid would also act on rna 2, subsequent studies have shown that aid can act as a cytosine deaminase on dna in escherichia coli. Replication protein a interacts with aid to promote. Class switch recombination and hypermutation require. Activationinduced cytidine deaminase definition of. These processes take place within germinal centers of secondary. Activationinduced cytidine deaminase aid is a singlestranded ss dna deaminase required for somatic hypermutation shm and class switch recombination of immunoglobulin genes. The enzymes cytidine deaminase domain introduces uracil residues into the.
Activationinduced cytidine deaminase aid, a protein necessary for somatic hypermutation and class switch recombination, is expressed in the germinal center 10 and in extrafollicular large proliferating b cells. Despite its importance in these transactions little is known about how aid finds its targets. Activationinduced cytidine deaminase targets dna at sites of rna polymerase ii stalling by interaction with spt5 rushad pavri,1 anna gazumyan,1,2 mila jankovic,1 michela di virgilio,1 isaac klein,1 camilo ansarahsobrinho,3 wolfgang resch, 3arito yamane, bernardo reina sanmartin,1,4 vasco barreto,1,5 thomas j. Activation induced cytidine deaminase aid is an essential regulator of b cell diversification, but its full range of action has until recently been an enigma. Here, we have proposed that activationinduced cytidine deaminase aid, encoded by aicda links chronic inflammation and skin cancer. Pdf activationinduced cytidine deaminase aid is critically involved in class switch recombination and somatic hypermutation of ig loci resulting in. A causal link between uvindependent skin cancers and chronic inflammation has been suspected, although the precise mechanism underlying this association is unclear. Specific expression of activationinduced cytidine deaminase aid, a novel member of the rnaediting.
Offtarget lesions can activate oncogenes or cause chromosome translocations. Biochemical regulatory features of activationinduced cytidine. Activationinduced cytidine deaminase aid promotes b. Activationinduced cytidine deaminase expression in cd4. Activationinduced cytidine deaminase targets dna at sites. Cytokines stimulate transcription through the ch gene and. Activation induced cytidine deaminase exhibits a processive behavior in vitro when catalyzing deaminations, much like that of rna and dna polymerases, in that it preferentially mutates dc on the same dna strand 59, but its behavior is more like that of restriction enzymes in that it tends to slide and jump along that strand 107. Activation induced cytidine deaminase aid, produced by the aicda gene, is essential for the immunoglobulin gene ig alterations that form immune memory. Apr 19, 2012 activationinduced cytidine deaminase aid is critically involved in class switch recombination and somatic hypermutation of ig loci resulting in diversification of antibodies repertoire and production of highaffinity antibodies and as such represents a physiological tool to introduce dna alterations. Biological function of activationinduced cytidine deaminase.
S2b were transfected into huh7 cells, which were then cultured for 3 d. This leads to a rearranged ch locus and deletion of the intervening sequence as an episomal circle. The cells dna replication machinery recognizes the u as a t. Rather, it functions by deaminating cytidine, and in this manner. Activation induced cytidine deaminase links ovulation induced inflammation and serous carcinogenesis. Activationinduced cytidine deaminase aid, a nucleotideediting enzyme that triggers dna alterations and doublestrand dna breaks in the immunoglobulin gene, has been identified in activated b lymphocytes. It creates mutations in dna by deamination of cytosine base, which turns it into uracil which is recognized as a thymine. Sapoznik s, baharshany k, brand h, pinto y, gabay o, glicksaar e et al. The dnarna editing enzyme activation induced cytidine deaminase aid is mutagenic and has been implicated in human tumorigenesis. Activationinduced cytidine deaminase deficiency causes.
Activationinduced cytidine deaminase aid is a dnamutating enzyme that is a member of the apolipoprotein b. Activationinduced cytidine deaminase aid is critically involved in class switch recombination and somatic hypermutation of ig loci resulting in diversification of antibodies repertoire and production of highaffinity antibodies and as such represents a physiological tool to introduce dna alterations. Activation induced cytidine deaminase aid is an essential enzyme for the processes of antibody affinity maturation and isotype switching. Upregulation of activationinduced cytidine deaminase causes.