AID in Antibody Diversification: There and Back Again

Overview

Journal Trends Immunol

Specialty Allergy & Immunology

Date 2020 May 22

PMID 32434680

Citations 69

Authors

Yuqing Feng

Noe Seija

Javier M Di Noia

Alberto Martin

Affiliations

Soon will be listed here.

Abstract

Activation-Induced cytidine Deaminase (AID) initiates affinity maturation and isotype switching by deaminating deoxycytidines within immunoglobulin genes, leading to somatic hypermutation (SHM) and class switch recombination (CSR). AID thus potentiates the humoral response to clear pathogens. Marking the 20th anniversary of the discovery of AID, we review the current understanding of AID function. We discuss AID biochemistry and how error-free forms of DNA repair are co-opted to prioritize mutagenesis over accuracy during antibody diversification. We discuss the regulation of DNA double-strand break (DSB) repair pathways during CSR. We describe genomic targeting of AID as a multilayered process involving chromatin architecture, cis- and trans-acting factors, and determining mutagenesis - distinct from AID occupancy at loci that are spared from mutation.

Citing Articles

Leong S, Nasser H, Ikeda T Int J Mol Sci. 2025; 26(4).

PMID: 40004025 PMC: 11855278. DOI: 10.3390/ijms26041561.

The LIM-domain-only protein LMO2 and its binding partner LDB1 are differentially required for class switch recombination.

Yang B, Guo Y, Liu L, Huang T, Zhao B, Bai W Proc Natl Acad Sci U S A. 2025; 122(4):e2412376122.

PMID: 39847321 PMC: 11789033. DOI: 10.1073/pnas.2412376122.

Turncoat antibodies unmasked in a model of autoimmune demyelination: from biology to therapy.

Taghipour-Mirakmahaleh R, Morin F, Zhang Y, Bourhoven L, Beland L, Zhou Q bioRxiv. 2024; .

PMID: 39677612 PMC: 11642901. DOI: 10.1101/2024.12.03.623846.

Discovery, recognized antigenic structures, and evolution of cross-serotype broadly neutralizing antibodies from porcine B-cell repertoires against foot-and-mouth disease virus.

Li F, Wu S, Lv L, Huang S, Zhang Z, Zerang Z PLoS Pathog. 2024; 20(10):e1012623.

PMID: 39405339 PMC: 11508087. DOI: 10.1371/journal.ppat.1012623.

Antibodies as key mediators of protection against .

Wang Q, Nag D, Baldwin S, Coler R, McNamara R Front Immunol. 2024; 15:1430955.

PMID: 39286260 PMC: 11402706. DOI: 10.3389/fimmu.2024.1430955.

References

Frieder D, Larijani M, Collins C, Shulman M, Martin A . The concerted action of Msh2 and UNG stimulates somatic hypermutation at A . T base pairs. Mol Cell Biol. 2009; 29(18):5148-57. PMC: 2738296. DOI: 10.1128/MCB.00647-09. View

Maul R, Cao Z, Venkataraman L, Giorgetti C, Press J, Denizot Y . Spt5 accumulation at variable genes distinguishes somatic hypermutation in germinal center B cells from ex vivo-activated cells. J Exp Med. 2014; 211(11):2297-306. PMC: 4203944. DOI: 10.1084/jem.20131512. View

Larijani M, Martin A . The biochemistry of activation-induced deaminase and its physiological functions. Semin Immunol. 2012; 24(4):255-63. DOI: 10.1016/j.smim.2012.05.003. View

Yeap L, Hwang J, Du Z, Meyers R, Meng F, Jakubauskaite A . Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes. Cell. 2015; 163(5):1124-1137. PMC: 4751889. DOI: 10.1016/j.cell.2015.10.042. View

Rothschild G, Zhang W, Lim J, Giri P, Laffleur B, Chen Y . Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination. Sci Immunol. 2020; 5(44). PMC: 7608691. DOI: 10.1126/sciimmunol.aay5864. View

Zeng X, Winter D, Kasmer C, Kraemer K, Lehmann A, Gearhart P . DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat Immunol. 2001; 2(6):537-41. DOI: 10.1038/88740. View

Wang X, Fan M, Kalis S, Wei L, Scharff M . A source of the single-stranded DNA substrate for activation-induced deaminase during somatic hypermutation. Nat Commun. 2014; 5:4137. PMC: 4154566. DOI: 10.1038/ncomms5137. View

Petersen S, Casellas R, Reina-San-Martin B, Chen H, Difilippantonio M, Wilson P . AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching. Nature. 2001; 414(6864):660-665. PMC: 4729367. DOI: 10.1038/414660a. View

Pham P, Malik S, Mak C, Calabrese P, Roeder R, Goodman M . AID-RNA polymerase II transcription-dependent deamination of IgV DNA. Nucleic Acids Res. 2019; 47(20):10815-10829. PMC: 6846656. DOI: 10.1093/nar/gkz821. View

10.

Duquette M, Pham P, Goodman M, Maizels N . AID binds to transcription-induced structures in c-MYC that map to regions associated with translocation and hypermutation. Oncogene. 2005; 24(38):5791-8. DOI: 10.1038/sj.onc.1208746. View

11.

Schatz D, Oettinger M, Baltimore D . The V(D)J recombination activating gene, RAG-1. Cell. 1989; 59(6):1035-48. DOI: 10.1016/0092-8674(89)90760-5. View

12.

Methot S, Litzler L, Subramani P, Eranki A, Fifield H, Patenaude A . A licensing step links AID to transcription elongation for mutagenesis in B cells. Nat Commun. 2018; 9(1):1248. PMC: 5871760. DOI: 10.1038/s41467-018-03387-6. View

13.

Zheng S, Vuong B, Vaidyanathan B, Lin J, Huang F, Chaudhuri J . Non-coding RNA Generated following Lariat Debranching Mediates Targeting of AID to DNA. Cell. 2015; 161(4):762-73. PMC: 4426339. DOI: 10.1016/j.cell.2015.03.020. View

14.

Masani S, Han L, Meek K, Yu K . Redundant function of DNA ligase 1 and 3 in alternative end-joining during immunoglobulin class switch recombination. Proc Natl Acad Sci U S A. 2016; 113(5):1261-6. PMC: 4747719. DOI: 10.1073/pnas.1521630113. View

15.

Pham P, Calabrese P, Park S, Goodman M . Analysis of a single-stranded DNA-scanning process in which activation-induced deoxycytidine deaminase (AID) deaminates C to U haphazardly and inefficiently to ensure mutational diversity. J Biol Chem. 2011; 286(28):24931-42. PMC: 3137067. DOI: 10.1074/jbc.M111.241208. View

16.

Pavri R . R Loops in the Regulation of Antibody Gene Diversification. Genes (Basel). 2017; 8(6). PMC: 5485518. DOI: 10.3390/genes8060154. View

17.

Halabelian L, Ravichandran M, Li Y, Zeng H, Rao A, Aravind L . Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition. Nat Struct Mol Biol. 2019; 26(7):607-612. PMC: 6609482. DOI: 10.1038/s41594-019-0246-6. View

18.

Cascalho M, Wong J, Steinberg C, Wabl M . Mismatch repair co-opted by hypermutation. Science. 1998; 279(5354):1207-10. DOI: 10.1126/science.279.5354.1207. View

19.

Parsa J, Ramachandran S, Zaheen A, Nepal R, Kapelnikov A, Belcheva A . Negative supercoiling creates single-stranded patches of DNA that are substrates for AID-mediated mutagenesis. PLoS Genet. 2012; 8(2):e1002518. PMC: 3276561. DOI: 10.1371/journal.pgen.1002518. View

20.

Ribeiro de Almeida C, Dhir S, Dhir A, Moghaddam A, Sattentau Q, Meinhart A . RNA Helicase DDX1 Converts RNA G-Quadruplex Structures into R-Loops to Promote IgH Class Switch Recombination. Mol Cell. 2018; 70(4):650-662.e8. PMC: 5971202. DOI: 10.1016/j.molcel.2018.04.001. View