Activation-induced cytidine deaminase explained

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.^[1] It creates mutations in DNA^{[2] [3]} 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 leads to B cell lymphoma.^[4]

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.^{[1] [5]}

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,^[6] and has been shown to require active transcription in order to exert its deaminating activity.^{[7] [8] [9]} 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.^[10]

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.^[11]

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.^[12]

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.^[13] At the post-transcriptional level of regulation, AID expression is silenced by mir-155, a small non-coding microRNA^{[14] [15]} controlled by IL-10 cytokine B cell signalling.^[16]

Clinical significance

Defects in this gene are associated with Hyper-IgM syndrome type 2.^[17] In certain haematological malignancies such as follicular lymphoma persistent AID expression has been linked to lymphomagenesis.^[18]

Further reading

• Wedekind JE, Dance GS, Sowden MP, Smith HC . Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business . Trends Genet. . 19 . 4 . 207–16 . 2003 . 12683974 . 10.1016/S0168-9525(03)00054-4 .
• Bransteitter R, Sneeden JL, Allen S, Pham P, Goodman MF . First AID (activation-induced cytidine deaminase) is needed to produce high affinity isotype-switched antibodies . J. Biol. Chem. . 281 . 25 . 16833–6 . 2006 . 16624806 . 10.1074/jbc.R600006200 . free .
• Muto T, Muramatsu M, Taniwaki M, Kinoshita K, Honjo T . Isolation, tissue distribution, and chromosomal localization of the human activation-induced cytidine deaminase (AID) gene . Genomics . 68 . 1 . 85–8 . 2001 . 10950930 . 10.1006/geno.2000.6268 .
• 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 . Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2) . Cell . 102 . 5 . 565–75 . 2000 . 11007475 . 10.1016/S0092-8674(00)00079-9 . 13092588 . 11655/14257 . free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Res. . 10 . 11 . 1788–95 . 2001 . 11076863 . 310948 . 10.1101/gr.143000 .
• 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 . Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome . Clin. Immunol. . 97 . 3 . 203–10 . 2001 . 11112359 . 10.1006/clim.2000.4956 .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–92 . 2001 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Noguchi E, Shibasaki M, Inudou M, Kamioka M, Yokouchi Y, Yamakawa-Kobayashi K, Hamaguchi H, Matsui A, Arinami T . 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 . 2001 . 11544457 . 10.1067/mai.2001.117456 .
• Martin A, Bardwell PD, Woo CJ, Fan M, Shulman MJ, Scharff MD . Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas . Nature . 415 . 6873 . 802–6 . 2002 . 11823785 . 10.1038/nature714 . 4349496 .
• Rada C, Jarvis JM, Milstein C . 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 . 2002 . 12011459 . 124518 . 10.1073/pnas.092160999 . 2002PNAS...99.7003R . free .
• Petersen-Mahrt SK, Harris RS, Neuberger MS . AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification . Nature . 418 . 6893 . 99–103 . 2002 . 12097915 . 10.1038/nature00862 . 2002Natur.418...99P . 4388160 .
• Dudley DD, Manis JP, Zarrin AA, Kaylor L, Tian M, Alt FW . 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 . 2002 . 12114543 . 126611 . 10.1073/pnas.152333499 . 2002PNAS...99.9984D . free .
• Martin A, Scharff MD . 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 . 2002 . 12202747 . 129440 . 10.1073/pnas.192442899 . 2002PNAS...9912304M . free .
• Greeve J, Philipsen A, Krause K, Klapper W, Heidorn K, Castle BE, Janda J, Marcu KB, Parwaresch R . Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas . Blood . 101 . 9 . 3574–80 . 2003 . 12511417 . 10.1182/blood-2002-08-2424 . free .
• Oppezzo P, Vuillier F, Vasconcelos Y, Dumas G, Magnac C, Payelle-Brogard B, Pritsch O, Dighiero G . Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation . Blood . 101 . 10 . 4029–32 . 2003 . 12521993 . 10.1182/blood-2002-10-3175 .
• Bransteitter R, Pham P, Scharff MD, Goodman MF . 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 . 2003 . 12651944 . 153055 . 10.1073/pnas.0730835100 . 2003PNAS..100.4102B . free .
• Zhu Y, Nonoyama S, Morio T, Muramatsu M, Honjo T, Mizutani S . Type two hyper-IgM syndrome caused by mutation in activation-induced cytidine deaminase . J. Med. Dent. Sci. . 50 . 1 . 41–6 . 2003 . 12715918 .
• Sohail A, Klapacz J, Samaranayake M, Ullah A, Bhagwat AS . Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations . Nucleic Acids Res. . 31 . 12 . 2990–4 . 2003 . 12799424 . 162340 . 10.1093/nar/gkg464 .

Notes and References

1. Web site: Entrez Gene: AICDA activation-induced cytidine deaminase.
2. 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. 10.1038/nature00862. 0028-0836. 12097915. 2002Natur.418...99P . 4388160.
3. Web site: Q9GZX7 (AICDA_HUMAN). 26 January 2013.
4. Lenz G, Staudt LM . Aggressive Lymphomas . N Engl J Med . 362 . 15 . 1417–29 . 2010 . 20393178 . 10.1056/NEJMra0807082 . 7316377 .
5. Sheppard EC, Morrish RB, Dillon MJ, Leyland R, Chahwan R . Epigenomic Modifications Mediating Antibody Maturation . Frontiers in Immunology . 9 . 355–372 . 2018 . 29535729 . 10.3389/fimmu.2018.00355. 5834911 . free .
6. Bransteitter R, Pham P, Scharff MD, Goodman MF . 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 . Apr 1, 2003 . 12651944 . 153055 . 10.1073/pnas.0730835100 . 2003PNAS..100.4102B . free .
7. Chaudhuri J, Tian M, Khuong C, Chua K, Pinaud E, Alt FW . Transcription-targeted DNA deamination by the AID antibody diversification enzyme . Nature . 422 . 6933 . 726–30 . Apr 17, 2003 . 12692563 . 10.1038/nature01574 . 2003Natur.422..726C . 771802 .
8. Sohail A, Klapacz J, Samaranayake M, Ullah A, Bhagwat AS . Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations . Nucleic Acids Research . 31 . 12 . 2990–4 . Jun 15, 2003 . 12799424 . 162340 . 10.1093/nar/gkg464 .
9. Ramiro AR, Stavropoulos P, Jankovic M, Nussenzweig MC . Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand . Nature Immunology . 4 . 5 . 452–6 . May 2003 . 12692548 . 10.1038/ni920 . 11431823 .
10. 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 . Convergent Transcription at Intragenic Super-Enhancers Targets AID-Initiated Genomic Instability . Cell . 159 . 7 . 1538–48 . 2014 . 25483776 . 10.1016/j.cell.2014.11.014 . 4322776.
11. Morgan HD, Dean W, Coker HA, Reik W, Petersen-Mahrt SK . Activation-induced Cytidine Deaminase Deaminates 5-Methylcytosine in DNA and Is Expressed in Pluripotent Tissues . J. Biol. Chem. . 279 . 50 . 52353–52360 . 2004 . 15448152 . 10.1074/jbc.M407695200 . free .
12. Sheppard EC, Morrish RB, Dillon MJ, Leyland R, Chahwan R . Epigenomic Modifications Mediating Antibody Maturation . Frontiers in Immunology . 9 . 355–372 . 2018 . 29535729 . 10.3389/fimmu.2018.00355. 5834911 . free .
13. Xu Z, Pone EJ, Al-Qahtani A, Park SR, Zan H, Casali P . Regulation of aicda expression and AID activity: relevance to somatic hypermutation and class switch DNA recombination . . 27 . 4 . 367–97 . 2007-01-01 . 18197815 . 2994649 . 10.1615/critrevimmunol.v27.i4.60.
14. 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 . MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation . Immunity . 28 . 5 . 630–8 . May 2008 . 18455451 . 2713656 . 10.1016/j.immuni.2008.04.002 .
15. Teng G, Hakimpour P, Landgraf P, Rice A, Tuschl T, Casellas R, Papavasiliou FN . MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase . Immunity . 28 . 5 . 621–9 . May 2008 . 18450484 . 2430982 . 10.1016/j.immuni.2008.03.015 .
16. Fairfax KA, Gantier MP, Mackay F, Williams BR, McCoy CE . IL-10 regulates Aicda expression through miR-155 . Journal of Leukocyte Biology . 97 . 1 . 71–8 . Jan 2015 . 25381386 . 10.1189/jlb.2A0314-178R . 9138000 .
17. Luo Z, Ronai D, Scharff MD . 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 . 2004 . 15480307 . 10.1016/j.jaci.2004.07.049 . free .
18. Scherer. F. Navarrete. MA. Bertinetti-Lapatki. C. Boehm. J. Schmitt-Graeff. A. Veelken. H. Isotype-switched follicular lymphoma displays dissociation between activation-induced cytidine deaminase expression and somatic hypermutation. Leukemia & Lymphoma. January 2016. 57. 1. 151–60. 25860234. 10.3109/10428194.2015.1037758. 31242381.