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Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity

Key Points

  • The immunoglobulin gene-modifying enzyme activation-induced cytidine deaminase (AID) promiscuously targets a defined subset of non-immunoglobulin loci, including oncogenes involved in B cell malignancies.

  • AID and related apolipoprotein B mRNA-editing catalytic (APOBEC) deaminases create large stretches of mutation patches in B cells and non-B cell tumours, respectively.

  • Super-enhancers attract AID off-target activity.

  • RNA processing through splicing and exosome-mediated degradation facilitates AID activity at the Igh locus.

  • The tightly controlled subcellular localization of AID limits off-target activity.

Abstract

As B cells engage in the immune response, they express activation-induced cytidine deaminase (AID) to initiate the hypermutation and recombination of immunoglobulin genes, which are crucial processes for the efficient recognition and disposal of pathogens. However, AID must be tightly controlled in B cells to minimize off-target mutations, which can drive chromosomal translocations and the development of B cell malignancies, such as lymphomas. Recent genomic and biochemical analyses have begun to unravel the mechanisms of how AID-mediated deamination is targeted outside immunoglobulin genes. Here, we discuss the transcriptional and topological features that are emerging as key drivers of AID promiscuous activity.

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Figure 1: Differential processing of AID lesions.
Figure 2: Super-enhancers are preferred targets of AID activity.
Figure 3: Potential mechanisms whereby the RNA exosome facilitates AID targeting.
Figure 4: RNA-mediated targeting of AID to S region DNA.
Figure 5: Integrative scheme of the mechanisms that regulate AID activity.

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Correspondence to Rafael Casellas or Javier M. Di Noia.

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Glossary

V(D)J recombination

Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antibody and T cell receptor proteins. The combinatorial nature of V(D)J recombination and the distribution of recombining genes in the vertebrate genome create repertoire diversity of B cell and T cell surface receptors.

Somatic hypermutation

(SHM). A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibody, SHM leads to affinity maturation of the antibody response in germinal centres.

Class-switch recombination

(CSR). A recombinational process that replaces the immunoglobulin heavy chain constant region Cμ (which encodes the Fc portion of IgM) for that of the downstream isotypes Cγ, Cα or Cε, which encode the constant region of IgG, IgA or IgE, respectively.

DNA deamination

Removal of an amine group from pyrimidine or purine nucleic-acid bases. Deamination of cytosine and adenosine yields uracil and inosine, respectively.

Base-excision repair

(BER). A DNA repair pathway that removes uridine nucleotides from DNA that arise by spontaneous or purposeful deamination of cytidines. Repair is initiated by uracil DNA glycosylase (UNG), which excises the uracil base, followed by cleavage of the abasic site by the apurinic apyrimidinic endonuclease 1 (APE1).

Mismatch repair

(MMR). A repair pathway that removes mismatched base pairs from DNA that result from errors made by replicative DNA polymerases or from deamination by activation-induced cytidine deaminase (AID) and apolipoprotein B mRNA-editing catalytic (APOBEC) deaminases. Repair involves the removal of a tract of DNA including the mismatch and re-copying of the complementary strand. This pathway is mediated by the proteins MSH2 and MSH6 among others.

Chromosomal translocations

Aberrant joining of DNA breaks from heterologous chromosomes that do not normally pair during mitosis or meiosis.

AID off-target activity

Promiscuous activation-induced cytidine deaminase (AID)-mediated deamination of genomic sites other than immunoglobulin gene loci.

Transition mutations

Base changes in DNA in which a C or T is replaced by a T or a C, respectively. A to G and G to A mutations are also transitions.

Enhancers

Regulatory DNA elements that recruit transcription factors, influence the rate of gene expression and function in an orientation- and position-independent manner (that is, they can function either upstream or downstream of the associated gene, or in an intron). They may associate with promoters through long-range chromatin interactions.

Non-homologous DNA end joining

(NHEJ). A repair pathway that joins broken DNA ends without depending on extended homology. Components of this pathway include the proteins KU70, KU80, artemis, X-ray repair cross-complementing protein 4 (XRCC4), DNA ligase IV and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs).

Homologous recombination

A DNA repair pathway that makes use of homologous sequences (for example, homologous chromosomes) as templates to repair a double-strand break. The process involves resection of DNA ends, recruitment of replication protein A (RPA) and RAD proteins, strand invasion of the intact sequence, DNA synthesis, ligation and resolution.

Kataegis

Clusters of mutations (mostly transitions) in the same DNA strand that are introduced in tumour genomes by cytidine deaminases: apolipoprotein B mRNA-editing catalytic (APOBEC) enzymes in non-B cell tumours and activation-induced cytidine deaminase (AID) in B cell lymphomas.

Chromothripsis

Clustered and massive chromosomal rearrangments in one or several chromosomes of primary or transformed cells. This process occurs as a result of a catastrophic event in the history of the cells and promotes tumour development and congenital diseases.

TET proteins

A family of ten-eleven-translocation (TET) proteins that catalyse the conversion of methylated cytidines to hydroxymethylated cytidines. This step initiates a series of catalytic events that lead to DNA demethylation.

Super-enhancer

A cluster of transcriptional regulatory elements (promoters and enhancers) associated by long-range chromatin loops. They tend to modulate gene expression as a unit.

RNA exosome complex

A multiprotein intracellular complex that degrades short RNA molecules in the 3′–5′ orientation.

xTSS-RNAs

Transcription start site (TSS)-associated antisense transcripts that can exceed 500 base pairs in length and are transcribed divergently from cognate coding genes. These RNAs are mostly degraded by the exosome complex.

G-quadruplexes

Non-B DNA structures that form at G-rich sequences. By means of Hoogsteen hydrogen bonding, four G bases create square planar structures known as G-quartets. Two or three G-quartets can stack on top of each other to form a quadruplex.

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Casellas, R., Basu, U., Yewdell, W. et al. Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity. Nat Rev Immunol 16, 164–176 (2016). https://doi.org/10.1038/nri.2016.2

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