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Chapter 15 : Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination

Authors: Joyce K. Hwang*1, Frederick W. Alt2, Leng-Siew Yeap*3
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Affiliations: 1: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children’s Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115; 2: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children’s Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115; 3: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children’s Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115
Content Type: Monograph
Publication Year: 2015

Category: Clinical Microbiology

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Abstract:

The B cell receptor (BCR) is expressed on the B lymphocyte cell surface where it serves as a receptor for foreign antigens ( ). The BCR is comprised of two immunoglobulin (Ig) heavy (IgH) chains encoded by the heavy chain locus and two Ig light (IgL) chains encoded by, for a given BCR, either the or (collectively referred to as ) light chain loci ( Fig. 1 ). These three loci lie on different chromosomes in both humans and mice. While there are certain differences in organization, the overall strategies for gene diversification in mice and humans are very much the same ( ), so this review will focus mainly on the mouse. The amino-terminal portions of the IgH and IgL chains have a highly variable amino acid sequence from species to species of antibody and are called variable (V) regions. The IgH and IgL variable regions interact to generate the antigen-binding portion of the BCR/antibody. The carboxy-terminal end of IgH and IgL chains have only a few variations in their sequences and thus are called constant (C) regions.

Citation: Hwang* J, Alt F, Yeap* L. 2015. Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination, p 325-348. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0037-2014
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Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination
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Citation: Hwang* J, Alt F, Yeap* L. 2015. Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination, p 325-348. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0037-2014
/content/10.1128/9781555819217.chap15.fig15-1
Figure 1
Antibody structure. The BCR is comprised of two immunoglobulin (Ig) heavy (IgH) chains encoded by the heavy chain locus and two Ig light (IgL) chains. The rectangles represent Ig domains that constitute the structural units of the immunoglobulin heavy and light chains. The variable regions are assembled through V(D)J recombination of V, D, and J gene segments on the heavy chain and V and J gene segments on the light chain. Complementarity-determining regions (CDRs) are indicated as regions in dashed red boxes: CDR 1 and 2 are encoded in the V or V gene segments, and CDR 3 is encoded by the V D J junctional region or V and J junctional region. The heavy and light chain variable regions form the antigen-binding site. The constant region determines the class and effector function of the antibody molecule.
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Figure 1

Antibody structure. The BCR is comprised of two immunoglobulin (Ig) heavy (IgH) chains encoded by the heavy chain locus and two Ig light (IgL) chains. The rectangles represent Ig domains that constitute the structural units of the immunoglobulin heavy and light chains. The variable regions are assembled through V(D)J recombination of V, D, and J gene segments on the heavy chain and V and J gene segments on the light chain. Complementarity-determining regions (CDRs) are indicated as regions in dashed red boxes: CDR 1 and 2 are encoded in the V or V gene segments, and CDR 3 is encoded by the V D J junctional region or V and J junctional region. The heavy and light chain variable regions form the antigen-binding site. The constant region determines the class and effector function of the antibody molecule.

Citation: Hwang* J, Alt F, Yeap* L. 2015. Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination, p 325-348. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0037-2014
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Figure 2
Genomic alterations of the locus. . Organization of the IgH constant (C) region. Each C region is preceded by a switch (S) region and a noncoding “I” exon. Blue oval between V(D)J exon and Iμ represents IgH intronic enhancer (iEμ). Blue oval downstream of Cα represents IgH 3′ regulatory region (IgH 3′RR). μ and δ mRNAs are shown below the corresponding genes. Dashed line represents spliced transcript. . AID generates point mutations and/or DNA double strand breaks (DSBs) at the V(D)J exon during somatic hypermutation (SHM). . AID-initiated DSBs in Sμ and Sγ1 result in CSR to IgG1. μ and γ1 germline transcripts are initiated from promoters upstream of the corresponding I exons.
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Figure 2

Genomic alterations of the locus. . Organization of the IgH constant (C) region. Each C region is preceded by a switch (S) region and a noncoding “I” exon. Blue oval between V(D)J exon and Iμ represents IgH intronic enhancer (iEμ). Blue oval downstream of Cα represents IgH 3′ regulatory region (IgH 3′RR). μ and δ mRNAs are shown below the corresponding genes. Dashed line represents spliced transcript. . AID generates point mutations and/or DNA double strand breaks (DSBs) at the V(D)J exon during somatic hypermutation (SHM). . AID-initiated DSBs in Sμ and Sγ1 result in CSR to IgG1. μ and γ1 germline transcripts are initiated from promoters upstream of the corresponding I exons.

Citation: Hwang* J, Alt F, Yeap* L. 2015. Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination, p 325-348. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0037-2014
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Figure 3
Mechanisms of AID cytidine deamination in SHM and CSR. AID deaminates cytidine (C) to uridines (U). The U/G lesion may be repaired with high fidelity (i.e. to C/G) by conventional base excision repair (BER) or mismatch repair (MMR). Mutagenic outcomes during SHM and CSR are generated by the following processes. . Replication over the U/G lesion produces transition mutations at C/G base pairs. . Uracil-DNA-Glycosylase (UNG) of the BER pathway excises the U creating an abasic site. Replication over the abasic site generates transition and transversion mutations at C/G base pairs. N indicates any nucleotide A,G,C, or T. AP endonuclease 1 (APE1) may create a nick at the abasic site. Nicks on both DNA strands may lead to DSBs. . MSH2-MSH6 of the mismatch repair pathway recognize the U/G mismatch. Exo1 excises the patch of DNA containing the mismatch. Error-prone polymerase resynthesizes the patch leading to spreading of mutations to A/T base pairs. Overlapping gaps may lead to DSBs.
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Figure 3

Mechanisms of AID cytidine deamination in SHM and CSR. AID deaminates cytidine (C) to uridines (U). The U/G lesion may be repaired with high fidelity (i.e. to C/G) by conventional base excision repair (BER) or mismatch repair (MMR). Mutagenic outcomes during SHM and CSR are generated by the following processes. . Replication over the U/G lesion produces transition mutations at C/G base pairs. . Uracil-DNA-Glycosylase (UNG) of the BER pathway excises the U creating an abasic site. Replication over the abasic site generates transition and transversion mutations at C/G base pairs. N indicates any nucleotide A,G,C, or T. AP endonuclease 1 (APE1) may create a nick at the abasic site. Nicks on both DNA strands may lead to DSBs. . MSH2-MSH6 of the mismatch repair pathway recognize the U/G mismatch. Exo1 excises the patch of DNA containing the mismatch. Error-prone polymerase resynthesizes the patch leading to spreading of mutations to A/T base pairs. Overlapping gaps may lead to DSBs.

Citation: Hwang* J, Alt F, Yeap* L. 2015. Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination, p 325-348. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0037-2014
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Figure 4
Transcriptional targeting of AID. R-loop structure. An R loop forms from G-rich RNA transcribed from the C-rich template strand forming a stable RNA-DNA hybrid with the C-rich template strand and looping out the G-rich nontemplate strand as ssDNA. A working model suggests that once AID is brought to a target via stalled Pol II and Spt5, the RNA exosome displaces or degrades the nascent RNA, thus making the template strand available for deamination, which may in vivo be further augmented by RPA association. Figure adapted from reference .
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Figure 4

Transcriptional targeting of AID. R-loop structure. An R loop forms from G-rich RNA transcribed from the C-rich template strand forming a stable RNA-DNA hybrid with the C-rich template strand and looping out the G-rich nontemplate strand as ssDNA. A working model suggests that once AID is brought to a target via stalled Pol II and Spt5, the RNA exosome displaces or degrades the nascent RNA, thus making the template strand available for deamination, which may in vivo be further augmented by RPA association. Figure adapted from reference .

Citation: Hwang* J, Alt F, Yeap* L. 2015. Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination, p 325-348. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0037-2014
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Figure 5
Outcomes of DSBs in S regions. DSBs within a S region may be directly joined back together or be joined back together following end resection, leading to intra-switch region deletions. Alternatively, a DSB generated in one S region may join to a DSB in another S region over a long-range (60 to 160 kb), which may lead to CSR. In addition, DSBs generated in an S region may participate in chromosomal translocations by joining to other non-S-region DSBs on the chromosome or to DSBs on other chromosomes.
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Figure 5

Outcomes of DSBs in S regions. DSBs within a S region may be directly joined back together or be joined back together following end resection, leading to intra-switch region deletions. Alternatively, a DSB generated in one S region may join to a DSB in another S region over a long-range (60 to 160 kb), which may lead to CSR. In addition, DSBs generated in an S region may participate in chromosomal translocations by joining to other non-S-region DSBs on the chromosome or to DSBs on other chromosomes.

Citation: Hwang* J, Alt F, Yeap* L. 2015. Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination, p 325-348. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0037-2014
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Figure 6
Synapsis and end-joining. The roles of synapsis and tethering in promoting long-range joining are shown. We propose that S regions are synapsed by diffusion, and that synapsis is possibly enhanced by proximity of S regions resulting from chromatin organization into megabase/submegabase domains. Post-cleavage, synapsis may be maintained by general DSB response (DSBR) factors, promoting the joining of S-region DSB ends by classical nonhomologous end-joining (C-NHEJ) and possibly alternative end-joining (A-EJ).
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Figure 6

Synapsis and end-joining. The roles of synapsis and tethering in promoting long-range joining are shown. We propose that S regions are synapsed by diffusion, and that synapsis is possibly enhanced by proximity of S regions resulting from chromatin organization into megabase/submegabase domains. Post-cleavage, synapsis may be maintained by general DSB response (DSBR) factors, promoting the joining of S-region DSB ends by classical nonhomologous end-joining (C-NHEJ) and possibly alternative end-joining (A-EJ).

Citation: Hwang* J, Alt F, Yeap* L. 2015. Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination, p 325-348. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0037-2014
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