Activation-induced cytidine deaminase
Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24
In B cells in the
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.[5][9]
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:
- 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
- Class switch recombination(CSR), in which B cells change their expression from IgM to IgG or other immune types
- Gene conversion (GC) a process that causes mutations in antibody genes of chickens, pigs and some other vertebrates.
AID has been shown
Recently, AICDA has been implicated in active DNA demethylation. AICDA can deaminate
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.[16]
- 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).
- The uracil may be excised by 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 phosphatebackbone. 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.
- The U:G mismatch may also be recognized by the . 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
Clinical significance
Defects in this gene are associated with Hyper-IgM syndrome type 2.[21] In certain haematological malignancies such as follicular lymphoma persistent AID expression has been linked to lymphomagenesis.[22]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000111732 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040627 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: AICDA activation-induced cytidine deaminase".
- S2CID 4388160.
- ^ "Q9GZX7 (AICDA_HUMAN)". Retrieved 26 January 2013.
- PMID 20393178.
- PMID 29535729.
- PMID 12651944.
- S2CID 771802.
- PMID 12799424.
- S2CID 11431823.
- PMID 25483776.
- PMID 15448152.
- PMID 29535729.
- PMID 18197815.
- PMID 18455451.
- PMID 18450484.
- S2CID 9138000.
- PMID 15480307.
- 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. 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. 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. 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. S2CID 13092588.
- Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.