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AICDA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5JJ4
Identifiers
Aliases	AICDA, AID, ARP2, CDA2, HEL-S-284, HIGM2, activation-induced cytidine deaminase, activation induced cytidine deaminase
External IDs	OMIM: 605257; MGI: 1342279; HomoloGene: 7623; GeneCards: AICDA; OMA:AICDA - orthologs
Gene location (Human) Chr. Chromosome 12 (human) Band 12p13.31 Start 8,602,155 bp End 8,613,242 bp
Gene location (Mouse) Chr. Chromosome 6 (mouse) Band 6|6 F1 Start 122,530,760 bp End 122,541,139 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell testicle lymph node appendix gonad tonsil mucosa of ileum epithelium of nasopharynx placenta gastric mucosa Top expressed in cumulus cell epithelium of female urethra ejaculatory duct epithelium of male urethra epithelium of vagina mesenteric lymph nodes muscle layer of ejaculatory duct granulocyte embryo muscle layer of seminal vesicle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amidines zinc ion binding protein binding catalytic activity hydrolase activity ubiquitin protein ligase binding metal ion binding cytidine deaminase activity identical protein binding RNA binding Cellular component exosome (RNase complex) nucleus cytoplasm P-body protein-containing complex Biological process somatic hypermutation of immunoglobulin genes DNA demethylation mRNA processing B cell differentiation somatic diversification of immunoglobulins negative regulation of DNA methylation-dependent heterochromatin assembly cytidine deamination cellular response to lipopolysaccharide isotype switching defense response to bacterium regulation of DNA stability negative regulation of transposition cytidine to uridine editing regulation of nuclear cell cycle DNA replication negative regulation of single stranded viral RNA replication via double stranded DNA intermediate defense response to virus DNA cytosine deamination Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 57379 11628 Ensembl ENSG00000111732 ENSMUSG00000040627 UniProt Q9GZX7 Q9WVE0 RefSeq (mRNA) NM_020661 NM_001330343 NM_009645 RefSeq (protein) NP_001317272 NP_065712 NP_033775 Location (UCSC) Chr 12: 8.6 – 8.61 Mb Chr 6: 122.53 – 122.54 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24 kDa enzyme which in humans is encoded by the AICDA gene. It creates mutations in DNA by deamination of cytosine base, which turns it into uracil (which is recognized as a thymine). In other words, it changes a C:G base pair into a U:G mismatch. The cell's DNA replication machinery recognizes the U as a T, and hence C:G is converted to a T:A base pair. During germinal center development of B lymphocytes, error-prone DNA repair following AID action also generates other types of mutations, such as C:G to A:T. AID is a member of the APOBEC family.

In B cells in the lymph nodes, AID causes mutations that produce antibody diversity, but that same mutation process can also lead to B cell lymphoma.

Function

This gene encodes a DNA-editing deaminase that is a member of the cytidine deaminase family. The protein is involved in somatic hypermutation, gene conversion, and class-switch recombination of immunoglobulin genes in B cells of the immune system.

AID is currently thought to be the master regulator of secondary antibody diversification. It is involved in the initiation of three separate immunoglobulin (Ig) diversification processes:

1. Somatic hypermutation (SHM), in which the antibody genes are minimally mutated to generate a library of antibody variants, some of which with higher affinity for a particular antigen than any of its close variants
2. Class switch recombination (CSR), in which B cells change their expression from IgM to IgG or other immune types
3. Gene conversion (GC) a process that causes mutations in antibody genes of chickens, pigs and some other vertebrates.

AID has been shown in vitro to be active on single-strand DNA, and has been shown to require active transcription in order to exert its deaminating activity. The involvement of Cis-regulatory factors is suspected as AID activity is several orders of magnitude higher in the immunoglobulin "variable" region than other regions of the genome that are known to be subject to AID activity. This is also true of artificial reporter constructs and transgenes that have been integrated into the genome. A recent publication suggests that high AID activity at a few non-immunoglobulin targets is achieved when transcription on opposite DNA strands converges due to super-enhancer activity.

Recently, AICDA has been implicated in active DNA demethylation. AICDA can deaminate 5-methylcytosine, which can then be replaced with cytosine by base excision repair.

Mechanism

AID is believed to initiate SHM in a multi-step mechanism. AID deaminates cytosine in the target DNA. Cytosines located within hotspot motifs are preferentially deaminated (WRCY motifs W=adenine or thymine, R=purine, C=cytosine, Y=pyrimidine, or the inverse RGYW G=guanine). The resultant U:G (U= uracil) mismatch is then subject to one of a number of fates.

1. The U:G mismatch is replicated across creating two daughter species, one that remains unmutated and one that undergoes a C => T transition mutation. (U is analogous to T in DNA and is treated as such when replicated).
2. The uracil may be excised by uracil-DNA glycosylase (UNG), resulting in an abasic site. This abasic site (or AP, apurinic/apyrimidinic) may be copied by a translesion synthesis DNA polymerase such as DNA polymerase eta, resulting in random incorporation of any of the four nucleotides, i.e. A, G, C, or T. Also, this abasic site may be cleaved by apurinic endonuclease (APE), creating a break in the deoxyribose phosphate backbone. This break can then lead to normal DNA repair, or, if two such breaks occur, one on either strand a staggered double-strand break can be formed (DSB). It is thought that the formation of these DSBs in either the switch regions or the Ig variable region can lead to CSR or GC, respectively.
3. The U:G mismatch may also be recognized by the DNA mismatch repair (MMR) machinery, to be specific by the MutSα(alpha) complex. MutSα is a heterodimer consisting of MSH2 and MSH6. This heterodimer is able to recognize mostly single-base distortions in the DNA backbone, consistent with U:G DNA mismatches. The recognition of U:G mistmatches by the MMR proteins is thought to lead to processing of the DNA through exonucleolytic activity to expose a single-strand region of DNA, followed by error prone DNA polymerase activity to fill in the gap. These error-prone polymerases are thought to introduce additional mutations randomly across the DNA gap. This allows the generation of mutations at AT base pairs.

The level of AID activity in B cells is tightly controlled by modulating AID expression. AID is induced by transcription factors TCF3 (E47), HoxC4, Irf8 and Pax5, and inhibited by PRDM1 (Blimp1) and Id2. At the post-transcriptional level of regulation, AID expression is silenced by mir-155, a small non-coding microRNA controlled by IL-10 cytokine B cell signalling.

Clinical significance

Defects in this gene are associated with Hyper-IgM syndrome type 2. In certain haematological malignancies such as follicular lymphoma persistent AID expression has been linked to lymphomagenesis.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000111732 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000040627 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. ^ "Entrez Gene: AICDA activation-induced cytidine deaminase".
6. Petersen-Mahrt, Svend K.; Harris, Reuben S.; Neuberger, Michael S. (2002-07-04). "AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification". Nature. 418 (6893): 99–103. Bibcode:2002Natur.418...99P. doi:10.1038/nature00862. ISSN 0028-0836. PMID 12097915. S2CID 4388160.
7. "Q9GZX7 (AICDA_HUMAN)". Retrieved 26 January 2013.
8. Lenz G, Staudt LM (2010). "Aggressive Lymphomas". N Engl J Med. 362 (15): 1417–29. doi:10.1056/NEJMra0807082. PMC 7316377. PMID 20393178.
9. Sheppard EC, Morrish RB, Dillon MJ, Leyland R, Chahwan R (2018). "Epigenomic Modifications Mediating Antibody Maturation". Frontiers in Immunology. 9: 355–372. doi:10.3389/fimmu.2018.00355. PMC 5834911. PMID 29535729.
10. Bransteitter R, Pham P, Scharff MD, Goodman MF (Apr 1, 2003). "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. 100 (7): 4102–7. Bibcode:2003PNAS..100.4102B. doi:10.1073/pnas.0730835100. PMC 153055. PMID 12651944.
11. Chaudhuri J, Tian M, Khuong C, Chua K, Pinaud E, Alt FW (Apr 17, 2003). "Transcription-targeted DNA deamination by the AID antibody diversification enzyme". Nature. 422 (6933): 726–30. Bibcode:2003Natur.422..726C. doi:10.1038/nature01574. PMID 12692563. S2CID 771802.
12. Sohail A, Klapacz J, Samaranayake M, Ullah A, Bhagwat AS (Jun 15, 2003). "Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations". Nucleic Acids Research. 31 (12): 2990–4. doi:10.1093/nar/gkg464. PMC 162340. PMID 12799424.
13. Ramiro AR, Stavropoulos P, Jankovic M, Nussenzweig MC (May 2003). "Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand". Nature Immunology. 4 (5): 452–6. doi:10.1038/ni920. PMID 12692548. S2CID 11431823.
14. Meng FL, Du Z, Federation A, Hu J, Wang Q, Kieffer-Kwon KR, Meyers RM, Amor C, Wasserman CR, Neuberg D, Casellas R, Nussenzweig MC, Bradner JE, Liu XS, Alt FW (2014). "Convergent Transcription at Intragenic Super-Enhancers Targets AID-Initiated Genomic Instability". Cell. 159 (7): 1538–48. doi:10.1016/j.cell.2014.11.014. PMC 4322776. PMID 25483776.
15. Morgan HD, Dean W, Coker HA, Reik W, Petersen-Mahrt SK (2004). "Activation-induced Cytidine Deaminase Deaminates 5-Methylcytosine in DNA and Is Expressed in Pluripotent Tissues". J. Biol. Chem. 279 (50): 52353–52360. doi:10.1074/jbc.M407695200. PMID 15448152.
16. Sheppard EC, Morrish RB, Dillon MJ, Leyland R, Chahwan R (2018). "Epigenomic Modifications Mediating Antibody Maturation". Frontiers in Immunology. 9: 355–372. doi:10.3389/fimmu.2018.00355. PMC 5834911. PMID 29535729.
17. Xu Z, Pone EJ, Al-Qahtani A, Park SR, Zan H, Casali P (2007-01-01). "Regulation of aicda expression and AID activity: relevance to somatic hypermutation and class switch DNA recombination". Critical Reviews in Immunology. 27 (4): 367–97. doi:10.1615/critrevimmunol.v27.i4.60. PMC 2994649. PMID 18197815.
18. Dorsett Y, McBride KM, Jankovic M, Gazumyan A, Thai TH, Robbiani DF, Di Virgilio M, Reina San-Martin B, Heidkamp G, Schwickert TA, Eisenreich T, Rajewsky K, Nussenzweig MC (May 2008). "MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation". Immunity. 28 (5): 630–8. doi:10.1016/j.immuni.2008.04.002. PMC 2713656. PMID 18455451.
19. Teng G, Hakimpour P, Landgraf P, Rice A, Tuschl T, Casellas R, Papavasiliou FN (May 2008). "MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase". Immunity. 28 (5): 621–9. doi:10.1016/j.immuni.2008.03.015. PMC 2430982. PMID 18450484.
20. Fairfax KA, Gantier MP, Mackay F, Williams BR, McCoy CE (Jan 2015). "IL-10 regulates Aicda expression through miR-155". Journal of Leukocyte Biology. 97 (1): 71–8. doi:10.1189/jlb.2A0314-178R. PMID 25381386. S2CID 9138000.
21. Luo Z, Ronai D, Scharff MD (2004). "The role of activation-induced cytidine deaminase in antibody diversification, immunodeficiency, and B-cell malignancies". J. Allergy Clin. Immunol. 114 (4): 726–35, quiz 736. doi:10.1016/j.jaci.2004.07.049. PMID 15480307.
22. Scherer, F; Navarrete, MA; Bertinetti-Lapatki, C; Boehm, J; Schmitt-Graeff, A; Veelken, H (January 2016). "Isotype-switched follicular lymphoma displays dissociation between activation-induced cytidine deaminase expression and somatic hypermutation". Leukemia & Lymphoma. 57 (1): 151–60. doi:10.3109/10428194.2015.1037758. PMID 25860234. S2CID 31242381.

Further reading

• Wedekind JE, Dance GS, Sowden MP, Smith HC (2003). "Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business". Trends Genet. 19 (4): 207–16. doi:10.1016/S0168-9525(03)00054-4. PMID 12683974.
• Bransteitter R, Sneeden JL, Allen S, Pham P, Goodman MF (2006). "First AID (activation-induced cytidine deaminase) is needed to produce high affinity isotype-switched antibodies". J. Biol. Chem. 281 (25): 16833–6. doi:10.1074/jbc.R600006200. PMID 16624806.
• Muto T, Muramatsu M, Taniwaki M, Kinoshita K, Honjo T (2001). "Isolation, tissue distribution, and chromosomal localization of the human activation-induced cytidine deaminase (AID) gene". Genomics. 68 (1): 85–8. doi:10.1006/geno.2000.6268. PMID 10950930.
• Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, Catalan N, Forveille M, Dufourcq-Labelouse R, Gennery A, Tezcan I, Ersoy F, Kayserili H, Ugazio AG, Brousse N, Muramatsu M, Notarangelo LD, Kinoshita K, Honjo T, Fischer A, Durandy A (2000). "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)". Cell. 102 (5): 565–75. doi:10.1016/S0092-8674(00)00079-9. hdl:11655/14257. PMID 11007475. S2CID 13092588.
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Minegishi Y, Lavoie A, Cunningham-Rundles C, Bédard PM, Hébert J, Côté L, Dan K, Sedlak D, Buckley RH, Fischer A, Durandy A, Conley ME (2001). "Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome". Clin. Immunol. 97 (3): 203–10. doi:10.1006/clim.2000.4956. PMID 11112359.
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (2001). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
• Noguchi E, Shibasaki M, Inudou M, Kamioka M, Yokouchi Y, Yamakawa-Kobayashi K, Hamaguchi H, Matsui A, Arinami T (2001). "Association between a new polymorphism in the activation-induced cytidine deaminase gene and atopic asthma and the regulation of total serum IgE levels". The Journal of Allergy and Clinical Immunology. 108 (3): 382–6. doi:10.1067/mai.2001.117456. PMID 11544457.
• Martin A, Bardwell PD, Woo CJ, Fan M, Shulman MJ, Scharff MD (2002). "Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas". Nature. 415 (6873): 802–6. doi:10.1038/nature714. PMID 11823785. S2CID 4349496.
• Rada C, Jarvis JM, Milstein C (2002). "AID-GFP chimeric protein increases hypermutation of Ig genes with no evidence of nuclear localization". Proceedings of the National Academy of Sciences of the United States of America. 99 (10): 7003–8. Bibcode:2002PNAS...99.7003R. doi:10.1073/pnas.092160999. PMC 124518. PMID 12011459.
• Petersen-Mahrt SK, Harris RS, Neuberger MS (2002). "AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification". Nature. 418 (6893): 99–103. Bibcode:2002Natur.418...99P. doi:10.1038/nature00862. PMID 12097915. S2CID 4388160.
• Dudley DD, Manis JP, Zarrin AA, Kaylor L, Tian M, Alt FW (2002). "Internal IgH class switch region deletions are position-independent and enhanced by AID expression". Proceedings of the National Academy of Sciences of the United States of America. 99 (15): 9984–9. Bibcode:2002PNAS...99.9984D. doi:10.1073/pnas.152333499. PMC 126611. PMID 12114543.
• Martin A, Scharff MD (2002). "Somatic hypermutation of the AID transgene in B and non-B cells". Proceedings of the National Academy of Sciences of the United States of America. 99 (19): 12304–8. Bibcode:2002PNAS...9912304M. doi:10.1073/pnas.192442899. PMC 129440. PMID 12202747.
• Greeve J, Philipsen A, Krause K, Klapper W, Heidorn K, Castle BE, Janda J, Marcu KB, Parwaresch R (2003). "Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas". Blood. 101 (9): 3574–80. doi:10.1182/blood-2002-08-2424. PMID 12511417.
• Oppezzo P, Vuillier F, Vasconcelos Y, Dumas G, Magnac C, Payelle-Brogard B, Pritsch O, Dighiero G (2003). "Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation". Blood. 101 (10): 4029–32. doi:10.1182/blood-2002-10-3175. PMID 12521993.
• Bransteitter R, Pham P, Scharff MD, Goodman MF (2003). "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. 100 (7): 4102–7. Bibcode:2003PNAS..100.4102B. doi:10.1073/pnas.0730835100. PMC 153055. PMID 12651944.
• Zhu Y, Nonoyama S, Morio T, Muramatsu M, Honjo T, Mizutani S (2003). "Type two hyper-IgM syndrome caused by mutation in activation-induced cytidine deaminase". J. Med. Dent. Sci. 50 (1): 41–6. PMID 12715918.
• Sohail A, Klapacz J, Samaranayake M, Ullah A, Bhagwat AS (2003). "Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations". Nucleic Acids Res. 31 (12): 2990–4. doi:10.1093/nar/gkg464. PMC 162340. PMID 12799424.

External links

• AICDA+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human AICDA genome location and AICDA gene details page in the UCSC Genome Browser.

• Biology

• Genes on human chromosome 12
• Enzymes
• EC 3.5.4
• Immune system