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Linking class-switch recombination with somatic hypermutation

Nature Reviews Molecular Cell Biology volume 2, pages 493–503 (2001)Cite this article

Key Points

  • The discovery of activation-induced cytidine deaminase (AID) has revealed that there is a molecular link between two apparently different genetic alteration events — class-switch recombination and somatic hypermutation — which take place in the immunoglobulin loci of antigen-stimulated B lymphocytes.

  • These findings led us to propose that the recognition and cleavage steps of the two events may be mediated by a similar or the same molecule.

  • Because AID seems to be an RNA-editing enzyme, these results also suggest that the complexity of mammalian genetic information may be enriched by an interplay between RNA editing and DNA modification.

Abstract

The recent discovery of a molecular link between two apparently different genetic alteration events — class-switch recombination and somatic hypermutation — has led to the idea that the recognition and cleavage of target DNA in these two events might be mediated by similar or identical molecules to those involved in RNA editing. This could mean that the complexity of mammalian genetic information may be enriched by an interplay between RNA editing and DNA modification.

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Figure 1: Immunoglobulin heavy-chain gene organization and its DNA alteration.
Figure 2: Accessibility model of class-switch recombination.
Figure 3: Artificial substrates of class-switch recombination.
Figure 4: Inversions and deletions at class-switch recombination junctions.
Figure 5: Structure of the target DNA in class-switch recombination and somatic hypermutation.
Figure 6: Model for the regulation of class-switch recombination and somatic hypermutation by AID.

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Acknowledgements

We are grateful to Y. Sakakibara, S. Takeda, A. Shimizu, S. Fagarasan, M. Muramatsu, T. Shinohara, K. Ikuta and H. Nagaoka for their critical reading of the manuscript. We also thank T. Nishikawa and R. Yamasaki for their preparation of the manuscript. This investigation is supported by the Center of Excellence Grant from the Ministry of Education, Science, Sports and Culture of Japan.

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  1. Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-Ku, 606-8501, Kyoto, Japan

    Kazuo Kinoshita & Tasuku Honjo

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RAG-1

RAG-2

IgM

IgD

IgE

AID

CD40

IL-4

CD40L

TGF-β

BCL-6

Pms2

Msh2

Mlh1

HIGM1

HIGM2

APOBEC-1

ACF

Adar2

Adar1

FURTHER INFORMATION

Computer program

Glossary

ENHANCER

A regulatory element of DNA that activates transcription from distant promoters, independent of position and orientation.

S REGION

A functional region of DNA where class-switch recombination occurs, comprising repetitive sequences of palindrome-rich motifs.

CD40

A cell-surface receptor that belongs to the tumour necrosis factor receptor superfamily and is expressed on B lymphocytes, dendritic cells, activated macrophages, monocytes and endothelial cells.

CD40L

CD40L (or CD154) is a ligand of CD40. It belongs to the tumour necrosis factor superfamily and is expressed on activated T lymphocytes, monocytes and natural killer cells.

TRANSFORMING GROWTH FACTOR β (TGF-β)

A cytokine that has pleiotropic functions in the cell. In class-switch recombination, it activates transcription from the Iα promoter, promoting IgA class switching.

PEYER'S PATCH

A small collection of lymphoid cells that appear in the submucosal tissue (lamina propria) of the small intestine, constituting the secondary lymphoid organ of the gut.

SECONDARY STRUCTURE

Atypical structure of DNA formed by intra-strand base-pairing, such as stem–loops.

STAGGERED NICK

A form of DNA double-stranded break that produces 3′- or 5′-protruding ends.

ERROR-PRONE REPAIR

A general term for the repair of various types of DNA lesion at the expense of fidelity.

COMPLEMENTARITY-DETERMINING REGION

(CDR). Segment in the variable region genes of immunoglobulins and T-cell receptors, corresponding to loops of polypeptide chains that shape the complementary surface to the contour of antigens.

TERMINAL DEOXYRIBONUCLEOTIDE TRANSFERASE

(TdT). An enzyme that adds non-templated nucleotides to a 3′-hydroxyl end of DNA.

LIPOPOLYSACCHARIDE

(LPS). A component of the outer wall of Gram-negative bacteria, consisting of a sugar chain and lipid adducts.

CHYLOMICRON

A lipoprotein involved in transfer of the lipids absorbed in the small intestine.

APOBEC-1 COMPLEMENTATION FACTOR (ACF)

An RNA binding subunit of an apolipoprotein B mRNA editing complex (editosome) that is required for conversion of mRNAs for the low-density lipoprotein component, ApoB100, to those for the chylomicron component, ApoB48.

DNA HELICASE

An enzyme that unwinds duplex DNA during replication, transcription, repair and recombination.

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Kinoshita, K., Honjo, T. Linking class-switch recombination with somatic hypermutation. Nat Rev Mol Cell Biol 2, 493–503 (2001). https://doi.org/10.1038/35080033

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