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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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References

/content/book/10.1128/9781555819217.chap15
1. Harwood NE,, Batista FD . 2008. New insights into the early molecular events underlying B cell activation. Immunity 28( 5) : 609– 619.[PubMed] [CrossRef]
2. Cobb RM,, Oestreich KJ,, Osipovich OA,, Oltz EM . 2006. Accessibility control of V(D)J recombination. Adv Immunol 91 : 45– 109.[PubMed] [CrossRef]
3. Pan-Hammarstrom Q,, Zhao Y,, Hammarstrom L . Class switch recombination: a comparison between mouse and human. Adv Immunol 93 : 1– 61.[PubMed] [CrossRef]
4. Schatz DG,, Swanson PC . 2011. V(D)J recombination: mechanisms of initiation. Annu Rev Genet 45 : 167– 202.[PubMed] [CrossRef]
5. Deriano L,, Roth DB . 2013. Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage. Annu Rev Genet 47 : 433– 455.[PubMed] [CrossRef]
6. Alt FW,, Zhang Y,, Meng FL,, Guo C,, Schwer B . 2013. Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell 152( 3) : 417– 429.[PubMed] [CrossRef]
7. Alt FW,, Baltimore D . 1982. Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH fusions. Proc Natl Acad Sci USA 79( 13) : 4118– 4122.[PubMed] [CrossRef]
8. Davis MM,, Bjorkman PJ . 1988. T-cell antigen receptor genes and T-cell recognition. Nature 334( 6181) : 395– 402.[PubMed] [CrossRef]
9. Di Noia JM,, Neuberger MS . 2007. Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem 76 : 1– 22.[PubMed] [CrossRef]
10. Stewart AK,, Schwartz RS . 1994. Immunoglobulin V regions and the B cell. Blood 83( 7) : 1717– 1730.[PubMed]
11. Roy AL,, Sen R,, Roeder RG . 2011. Enhancer-promoter communication and transcriptional regulation of Igh. Trends Immunol 32( 11) : 532– 539.[PubMed] [CrossRef]
12. Muramatsu M,, Nagaoka H,, Shinkura R,, Begum NA,, Honjo T . 2007. Discovery of activation-induced cytidine deaminase, the engraver of antibody memory. Adv Immunol 94 : 1– 36.[PubMed] [CrossRef]
13. Pinaud E,, Marquet M,, Fiancette R,, Peron S,, Vincent-Fabert C,, Denizot Y,, Cogne M . 2011. The IgH locus 3′ regulatory region: pulling the strings from behind. Adv Immunol 110 : 27– 70.[PubMed] [CrossRef]
14. Chen K,, Cerutti A . 2010. New insights into the enigma of immunoglobulin D. Immunol Rev 237( 1) : 160– 179.[PubMed] [CrossRef]
15. Alt FW,, Yancopoulos GD,, Blackwell TK,, Wood C,, Thomas E,, Boss M,, Coffman R,, Rosenberg N,, Tonegawa S,, Baltimore D . 1984. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J 3( 6) : 1209– 1219.[PubMed]
16. Mostoslavsky R,, Alt RW,, Rajewsky K . 2004. The lingering enigma of the allelic exclusion mechanism. Cell 118( 5) : 539– 544.[PubMed] [CrossRef]
17. Chaudhuri J,, Basu U,, Zarrin A,, Yan C,, Franco S,, Perlot T,, Vuong B,, Wang J,, Phan RT,, Datta A,, Manis J,, Alt FW . 2007. Evolution of the immunoglobulin heavy chain class switch recombination mechanism. Adv Immunol 94 : 157– 214.[PubMed] [CrossRef]
18. Victora GD,, Nussenzweig MC . 2012. Germinal centers. Annu Rev Immunol 30 : 429– 457.[PubMed] [CrossRef]
19. Fagarasan S,, Kawamoto S,, Kanagawa O,, Suzuki K . 2010. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu Rev Immunol 28 : 243– 273.[PubMed] [CrossRef]
20. Stavnezer J,, Guikema JE,, Schrader CE . 2008. Mechanism and regulation of class switch recombination. Annu Rev Immunol 26 : 261– 292.[PubMed] [CrossRef]
21. Muramatsu M,, Kinoshita K,, Fagarasan S,, Yamada S,, Shinkai Y,, Honjo T . 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102( 5) : 553– 563.[PubMed] [CrossRef]
22. 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– 575.[PubMed] [CrossRef]
23. Wilson PC,, de Bouteiller O,, Liu YJ,, Potter K,, Banchereau J,, Capra JD,, Pascual V . 1998. Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes. J Exp Med 187( 1) : 59– 70.[PubMed] [CrossRef]
24. Goossens T,, Klein U,, Kuppers R . 1998. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc Natl Acad Sci USA 95( 5) : 2463– 2468.[PubMed] [CrossRef]
25. Rada C,, Williams GT,, Nilsen H,, Barnes DE,, Lindahl T,, Neuberger MS . 2002. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr Biol 12( 20) : 1748– 1755.[PubMed] [CrossRef]
26. Maul RW,, Gearhart PJ . 2010. AID and somatic hypermutation. Adv Immunol 105 : 159– 191.[PubMed] [CrossRef]
27. Peled JU,, Kuang FL,, Iglesias-Ussel MD,, Roa S,, Kalis SL,, Goodman MF,, Scharff MD . 2008. The biochemistry of somatic hypermutation. Annu Rev Immunol 26 : 481– 511.[PubMed] [CrossRef]
28. Matthews AJ,, Zheng S,, DiMenna LJ,, Chaudhuri J . 2014. Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair. Adv Immunol 122 : 1– 57.[PubMed] [CrossRef]
29. Woof JM,, Kerr MA . 2006. The function of immunoglobulin A in immunity. J Pathol 208( 2) : 270– 282.[PubMed] [CrossRef]
30. Wu LC,, Zarrin AA . 2014. The production and regulation of IgE by the immune system. Nat Rev Immunol 14( 4) : 247– 259.[PubMed] [CrossRef]
31. Nimmerjahn F,, Ravetch JV . 2008. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8( 1) : 34– 47.[PubMed] [CrossRef]
32. Muramatsu M,, Sankaranand VS,, Anant S,, Sugai M,, Kinoshita K,, Davidson NO,, Honjo T . 1999. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J Biol Chem 274( 26) : 18470– 18476.[PubMed] [CrossRef]
33. Arakawa H,, Hauschild J,, Buerstedde JM . 2002. Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion. Science 295( 5558) : 1301– 1306.[PubMed] [CrossRef]
34. 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. Proc Natl Acad Sci USA 100( 7) : 4102– 4107.[PubMed] [CrossRef]
35. Chaudhuri J,, Tian M,, Khuong C,, Chua K,, Pinaud E,, Alt FW . 2003. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422( 6933) : 726– 730.[PubMed] [CrossRef]
36. Dickerson SK,, Market E,, Besmer E,, Papavasiliou FN . 2003. AID mediates hypermutation by deaminating single stranded DNA. J Exp Med 197( 10) : 1291– 1296.[PubMed] [CrossRef]
37. Pham P,, Bransteitter R,, Petruska J,, Goodman MF . 2003. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 424( 6944) : 103– 107.[PubMed] [CrossRef]
38. Rogozin IB,, Diaz M . 2004. Cutting edge: DGYW/WRCH is a better predictor of mutability at G:C bases in Ig hypermutation than the widely accepted RGYW/WRCY motif and probably reflects a two-step activation-induced cytidine deaminase-triggered process. J Immunol 172( 6) : 3382– 3384.[CrossRef]
39. Hackney JA,, Misaghi S,, Senger K,, Garris C,, Sun Y,, Lorenzo MN,, Zarrin AA . 2009. DNA targets of AID evolutionary link between antibody somatic hypermutation and class switch recombination. Adv Immunol 101 : 163– 189.[PubMed] [CrossRef]
40. Dorner T,, Brezinschek HP,, Brezinschek RI,, Foster SJ,, Domiati-Saad R,, Lipsky PE . 1997. Analysis of the frequency and pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes. J Immunol 158( 6) : 2779– 2789.[PubMed]
41. Rogozin IB,, Kolchanov NA . 1992. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. Biochim Biophys Acta 1171( 1) : 11– 18.[PubMed] [CrossRef]
42. Liu M,, Duke JL,, Richter DJ,, Vinuesa CG,, Goodnow CC,, Kleinstein SH,, Schatz DG . 2008. Two levels of protection for the B cell genome during somatic hypermutation. Nature 451( 7180) : 841– 845.[PubMed] [CrossRef]
43. Krokan HE,, Bjoras M . 2013. Base excision repair. Cold Spring Harbor Perspect Biol 5( 4) : a012583. [PubMed] [CrossRef]
44. Robertson AB,, Klungland A,, Rognes T,, Leiros I . 2009. DNA repair in mammalian cells: Base excision repair: the long and short of it. Cell Mol Life Sci 66( 6) : 981– 993.[PubMed] [CrossRef]
45. Jiricny J . 2006. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 7( 5) : 335– 346.[PubMed] [CrossRef]
46. Saribasak H,, Gearhart PJ . 2012. Does DNA repair occur during somatic hypermutation? Semin Immunol 24( 4) : 287– 292.[PubMed] [CrossRef]
47. Neuberger MS,, Di Noia JM,, Beale RC,, Williams GT,, Yang Z,, Rada C . 2005. Somatic hypermutation at A.T pairs: polymerase error versus dUTP incorporation. Nat Rev Immunol 5( 2) : 171– 178.[PubMed] [CrossRef]
48. Neuberger MS,, Rada C . 2007. Somatic hypermutation: activation-induced deaminase for C/G followed by polymerase eta for A/T. J Exp Med 204( 1) : 7– 10.[PubMed] [CrossRef]
49. Wiesendanger M,, Kneitz B,, Edelmann W,, Scharff MD . 2000. Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern. J Exp Med 191( 3) : 579– 584.[PubMed] [CrossRef]
50. Shen HM,, Tanaka A,, Bozek G,, Nicolae D,, Storb U . 2006. Somatic hypermutation and class switch recombination in Msh6(-/-)Ung(-/-) double-knockout mice. J Immunol 177( 8) : 5386– 5392.[PubMed] [CrossRef]
51. Bardwell PD,, Woo CJ,, Wei K,, Li Z,, Martin A,, Sack SZ,, Parris T,, Edelmann W,, Scharff MD . 2004. Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1-mutant mice. Nat Immunol 5( 2) : 224– 229.[PubMed] [CrossRef]
52. Zeng X,, Winter DB,, Kasmer C,, Kraemer KH,, Lehmann AR,, Gearhart PJ . 2001. DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat Immunol 2( 6) : 537– 541.[PubMed] [CrossRef]
53. Delbos F,, Aoufouchi S,, Faili A,, Weill JC,, Reynaud CA . 2007. DNA polymerase eta is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse. J Exp Med 204( 1) : 17– 23.[PubMed] [CrossRef]
54. 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.[PubMed] [CrossRef]
55. Rada C,, Di Noia JM,, Neuberger MS . 2004. Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation. Mol Cell 16( 2) : 163– 171.[PubMed] [CrossRef]
56. Chahwan R,, Edelmann W,, Scharff MD,, Roa S . 2012. AIDing antibody diversity by error-prone mismatch repair. Semin Immunol 24( 4) : 293– 300.[PubMed] [CrossRef]
57. Xue K,, Rada C,, Neuberger MS . 2006. The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2-/- ung-/- mice. J Exp Med 203( 9) : 2085– 2094.[PubMed] [CrossRef]
58. Neuberger MS . 2008. Antibody diversification by somatic mutation: from Burnet onwards. Immunol Cell Biol 86( 2) : 124– 132.[PubMed] [CrossRef]
59. Pech M,, Hochtl J,, Schnell H,, Zachau HG . 1981. Differences between germ-line and rearranged immunoglobulin V kappa coding sequences suggest a localized mutation mechanism. Nature 291( 5817) : 668– 670.[PubMed] [CrossRef]
60. Roes J,, Huppi K,, Rajewsky K,, Sablitzky F . 1989. V gene rearrangement is required to fully activate the hypermutation mechanism in B cells. J Immunol 142( 3) : 1022– 1026.[PubMed]
61. Lam KP,, Kuhn R,, Rajewsky K . 1997. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90( 6) : 1073– 1083.[PubMed] [CrossRef]
62. Betz AG,, Neuberger MS,, Milstein C . 1993. Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol Today 14( 8) : 405– 411.[PubMed] [CrossRef]
63. Betz AG,, Rada C,, Pannell R,, Milstein C,, Neuberger MS . 1993. Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots. Proc Natl Acad Sci USA 90( 6) : 2385– 2388.[PubMed] [CrossRef]
64. Jolly CJ,, Wagner SD,, Rada C,, Klix N,, Milstein C,, Neuberger MS . 1996. The targeting of somatic hypermutation. Semin Immunol 8( 3) : 159– 168.[PubMed] [CrossRef]
65. Wagner SD,, Milstein C,, Neuberger MS . 1995. Codon bias targets mutation. Nature 376( 6543) : 732. [PubMed] [CrossRef]
66. Kepler TB . 1997. Codon bias and plasticity in immunoglobulins. Mol Biol Evol 14( 6) : 637– 643.[PubMed] [CrossRef]
67. Foster SJ,, Dorner T,, Lipsky PE . 1999. Somatic hypermutation of VkappaJkappa rearrangements: targeting of RGYW motifs on both DNA strands and preferential selection of mutated codons within RGYW motifs. Eur J Immunol 29( 12) : 4011– 4021.[PubMed] [CrossRef]
68. Rada C,, Milstein C . 2001. The intrinsic hypermutability of antibody heavy and light chain genes decays exponentially. EMBO J 20( 16) : 4570– 4576.[PubMed] [CrossRef]
69. Yelamos J,, Klix N,, Goyenechea B,, Lozano F,, Chui YL,, Gonzalez Fernandez A,, Pannell R,, Neuberger MS,, Milstein C . 1995. Targeting of non-Ig sequences in place of the V segment by somatic hypermutation. Nature 376( 6537) : 225– 229.[PubMed] [CrossRef]
70. Azuma T,, Motoyama N,, Fields LE,, Loh DY . 1993. Mutations of the chloramphenicol acetyl transferase transgene driven by the immunoglobulin promoter and intron enhancer. Int Immunol 5( 2) : 121– 130.[PubMed] [CrossRef]
71. Peters A,, Storb U . 1996. Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 4( 1) : 57– 65.[PubMed] [CrossRef]
72. Bross L,, Fukita Y,, McBlane F,, Demolliere C,, Rajewsky K,, Jacobs H . 2000. DNA double-strand breaks in immunoglobulin genes undergoing somatic hypermutation. Immunity 13( 5) : 589– 597.[PubMed] [CrossRef]
73. Boboila C,, Jankovic M,, Yan CT,, Wang JH,, Wesemann DR,, Zhang T,, Fazeli A,, Feldman L,, Nussenzweig A,, Nussenzweig M,, Alt FW . 2010. Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci USA 107( 7) : 3034– 3039.[PubMed] [CrossRef]
74. Briney BS,, Willis JR,, Crowe EF Jr . 2012. Location and length distribution of somatic hypermutation-associated DNA insertions and deletions reveals regions of antibody structural plasticity. Genes Immun 13( 7) : 523– 529.[PubMed] [CrossRef]
75. Weiss U,, Zoebelein R,, Rajewsky K . 1992. Accumulation of somatic mutants in the B cell compartment after primary immunization with a T cell-dependent antigen. Eur J Immunol 22( 2) : 511– 517.[PubMed] [CrossRef]
76. Lebecque SG,, Gearhart PJ . 1990. Boundaries of somatic mutation in rearranged immunoglobulin genes: 5′ boundary is near the promoter, and 3′ boundary is approximately 1 kb from V(D)J gene. J Exp Med 172( 6) : 1717– 1727.[PubMed] [CrossRef]
77. Wu X,, Zhou T,, Zhu J,, Zhang B,, Georgiev I,, Wang C,, Chen X,, Longo NS,, Louder M,, McKee K,, O’Dell S,, Perfetto S,, Schmidt SD,, Shi W,, Wu L,, Yang Y,, Yang ZY,, Yang Z,, Zhang Z,, Bonsignori M,, Crump JA,, Kapiga SH,, Sam NE,, Haynes BF,, Simek M,, Burton DR,, Koff WC,, Doria-Rose NA,, Connors M,, Program NCS,, Mullikin JC,, Nabel GJ,, Roederer M,, Shapiro L,, Kwong PD,, Mascola JR . 2011. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333( 6049) : 1593– 1602.[PubMed] [CrossRef]
78. Mascola JR,, Haynes BF . 2013. HIV-1 neutralizing antibodies: understanding nature’s pathways. Immunol Rev 254( 1) : 225– 244.[PubMed] [CrossRef]
79. Kuppers R,, Dalla-Favera R . 2001. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20( 40) : 5580– 5594.[PubMed] [CrossRef]
80. Gostissa M,, Alt FW,, Chiarle R . 2011. Mechanisms that promote and suppress chromosomal translocations in lymphocytes. Annu Rev Immunol 29 : 319– 350.[PubMed] [CrossRef]
81. Storb U . 2014. Why does somatic hypermutation by AID require transcription of its target genes? Adv Immunol 122 : 253– 277.[PubMed] [CrossRef]
82. Odegard VH,, Schatz DG . 2006. Targeting of somatic hypermutation. Nat Rev Immunol 6( 8) : 573– 583.[PubMed] [CrossRef]
83. Fukita Y,, Jacobs H,, Rajewsky K . 1998. Somatic hypermutation in the heavy chain locus correlates with transcription. Immunity 9( 1) : 105– 114.[PubMed] [CrossRef]
84. Betz AG,, Milstein C,, Gonzalez-Fernandez A,, Pannell R,, Larson T,, Neuberger MS . 1994. Elements regulating somatic hypermutation of an immunoglobulin kappa gene: critical role for the intron enhancer/matrix attachment region. Cell 77( 2) : 239– 248.[PubMed] [CrossRef]
85. Tumas-Brundage K,, Manser T . 1997. The transcriptional promoter regulates hypermutation of the antibody heavy chain locus. J Exp Med 185( 2) : 239– 250.[PubMed] [CrossRef]
86. Sharpe MJ,, Milstein C,, Jarvis JM,, Neuberger MS . 1991. Somatic hypermutation of immunoglobulin kappa may depend on sequences 3′ of C kappa and occurs on passenger transgenes. EMBO J 10( 8) : 2139– 2145.[PubMed]
87. Terauchi A,, Hayashi K,, Kitamura D,, Kozono Y,, Motoyama N,, Azuma T . 2001. A pivotal role for DNase I-sensitive regions 3b and/or 4 in the induction of somatic hypermutation of IgH genes. J Immunol 167( 2) : 811– 820.[PubMed] [CrossRef]
88. Inlay MA,, Gao HH,, Odegard VH,, Lin T,, Schatz DG,, Xu Y . 2006. Roles of the Ig kappa light chain intronic and 3′ enhancers in Igk somatic hypermutation. J Immunol 177( 2) : 1146– 1151.[PubMed] [CrossRef]
89. van der Stoep N,, Gorman JR,, Alt FW . 1998. Reevaluation of 3′Ekappa function in stage- and lineage-specific rearrangement and somatic hypermutation. Immunity 8( 6) : 743– 750.[PubMed] [CrossRef]
90. Perlot T,, Alt FW,, Bassing CH,, Suh H,, Pinaud E . 2005. Elucidation of IgH intronic enhancer functions via germ-line deletion. Proc Natl Acad Sci USA 102( 40) : 14362– 14367.[PubMed] [CrossRef]
91. Pinaud E,, Khamlichi AA,, Le Morvan C,, Drouet M,, Nalesso V,, Le Bert M,, Cogne M . 2001. Localization of the 3′ IgH locus elements that effect long-distance regulation of class switch recombination. Immunity 15( 2) : 187– 199.[PubMed] [CrossRef]
92. Morvan CL,, Pinaud E,, Decourt C,, Cuvillier A,, Cogne M . 2003. The immunoglobulin heavy-chain locus hs3b and hs4 3′ enhancers are dispensable for VDJ assembly and somatic hypermutation. Blood 102( 4) : 1421– 1427.[PubMed] [CrossRef]
93. Vincent-Fabert C,, Fiancette R,, Pinaud E,, Truffinet V,, Cogne N,, Cogne M,, Denizot Y . 2010. Genomic deletion of the whole IgH 3′ regulatory region (hs3a, hs1,2, hs3b, and hs4) dramatically affects class switch recombination and Ig secretion to all isotypes. Blood 116( 11) : 1895– 1898.[PubMed] [CrossRef]
94. Rouaud P,, Vincent-Fabert C,, Saintamand A,, Fiancette R,, Marquet M,, Robert I,, Reina-San-Martin B,, Pinaud E,, Cogne M,, Denizot Y . 2013. The IgH 3′ regulatory region controls somatic hypermutation in germinal center B cells. J Exp Med 210( 8) : 1501– 1507.[PubMed] [CrossRef]
95. Buerstedde JM,, Alinikula J,, Arakawa H,, McDonald JJ,, Schatz DG . 2014. Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. PLoS Biol 12( 4) : e1001831. [PubMed] [CrossRef]
96. Xu Z,, Zan H,, Pone EJ,, Mai T,, Casali P . 2012. Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat Rev Immunol 12( 7) : 517– 31.[PubMed] [CrossRef]
97. Daniel JA,, Nussenzweig A . 2013. The AID-induced DNA damage response in chromatin. Mol Cell 50( 3) : 309– 321.[PubMed] [CrossRef]
98. Pavri R,, Gazumyan A,, Jankovic M,, Di Virgilio M,, Klein I,, Ansarah-Sobrinho C,, Resch W,, Yamane A,, Reina San-Martin B,, Barreto V,, Nieland TJ,, Root DE,, Casellas R,, Nussenzweig MC . 2010. Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5. Cell 143( 1) : 122– 133.[PubMed] [CrossRef]
99. Wada T,, Takagi T,, Yamaguchi Y,, Ferdous A,, Imai T,, Hirose S,, Sugimoto S,, Yano K,, Hartzog GA,, Winston F,, Buratowski S,, Handa H . 1998. DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev 12( 3) : 343– 356.[PubMed] [CrossRef]
100. Hartzog GA,, Wada T,, Handa H,, Winston F . 1998. Evidence that Spt4, Spt5, and Spt6 control transcription elongation by RNA polymerase II in Saccharomyces cerevisiae. Genes Dev 12( 3) : 357– 369.[PubMed] [CrossRef]
101. Chaudhuri J,, Khuong C,, Alt FW . 2004. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430( 7003) : 992– 998.[PubMed] [CrossRef]
102. Cheng HL,, Vuong BQ,, Basu U,, Franklin A,, Schwer B,, Astarita J,, Phan RT,, Datta A,, Manis J,, Alt FW,, Chaudhuri J . 2009. Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice. Proc Natl Acad Sci USA 106( 8) : 2717– 2722.[PubMed] [CrossRef]
103. McBride KM,, Gazumyan A,, Woo EM,, Schwickert TA,, Chait BT,, Nussenzweig MC . 2008. Regulation of class switch recombination and somatic mutation by AID phosphorylation. J Exp Med 205( 11) : 2585– 2594.[PubMed] [CrossRef]
104. Basu U,, Meng FL,, Keim C,, Grinstein V,, Pefanis E,, Eccleston J,, Zhang T,, Myers D,, Wasserman CR,, Wesemann DR,, Januszyk K,, Gregory RI,, Deng H,, Lima CD,, Alt FW . 2011. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell 144( 3) : 353– 363.[PubMed] [CrossRef]
105. Houseley J,, LaCava J,, Tollervey D . 2006. RNA-quality control by the exosome. Nat Rev Mol Cell Biol 7( 7) : 529– 539.[PubMed] [CrossRef]
106. Shen HM,, Storb U . 2004. Activation-induced cytidine deaminase (AID) can target both DNA strands when the DNA is supercoiled. Proc Natl Acad Sci USA 101( 35) : 12997– 13002.[PubMed] [CrossRef]
107. Longerich S,, Basu U,, Alt F,, Storb U . 2006. AID in somatic hypermutation and class switch recombination. Curr Opin Immunol 18( 2) : 164– 174.[PubMed] [CrossRef]
108. Pasqualucci L,, Migliazza A,, Fracchiolla N,, William C,, Neri A,, Baldini L,, Chaganti RS,, Klein U,, Kuppers R,, Rajewsky K,, Dalla-Favera R . 1998. BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci USA 95( 20) : 11816– 11821.[PubMed] [CrossRef]
109. Pasqualucci L,, Neumeister P,, Goossens T,, Nanjangud G,, Chaganti RS,, Kuppers R,, Dalla-Favera R . 2001. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412( 6844) : 341– 346.[PubMed] [CrossRef]
110. Shen HM,, Peters A,, Baron B,, Zhu X,, Storb U . 1998. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280( 5370) : 1750– 1752.[PubMed] [CrossRef]
111. Kohler KM,, McDonald JJ,, Duke JL,, Arakawa H,, Tan S,, Kleinstein SH,, Buerstedde JM,, Schatz DG . 2012. Identification of core DNA elements that target somatic hypermutation. J Immunol 189( 11) : 5314– 5326.[PubMed] [CrossRef]
112. Blagodatski A,, Batrak V,, Schmidl S,, Schoetz U,, Caldwell RB,, Arakawa H,, Buerstedde JM . 2009. A cis-acting diversification activator both necessary and sufficient for AID-mediated hypermutation. PLoS Genet 5( 1) : e1000332. [PubMed] [CrossRef]
113. Zhang T,, Franklin A,, Boboila C,, McQuay A,, Gallagher MP,, Manis JP,, Khamlichi AA,, Alt FW . 2010. Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regions. Proc Natl Acad Sci USA 107( 7) : 3040– 3045.[PubMed] [CrossRef]
114. Lutzker S,, Rothman P,, Pollock R,, Coffman R,, Alt FW . 1988. Mitogen- and IL-4-regulated expression of germ-line Ig gamma 2b transcripts: evidence for directed heavy chain class switching. Cell 53( 2) : 177– 184.[PubMed] [CrossRef]
115. Rothman P,, Chen YY,, Lutzker S,, Li SC,, Stewart V,, Coffman R,, Alt FW . 1990. Structure and expression of germ line immunoglobulin heavy-chain epsilon transcripts: interleukin-4 plus lipopolysaccharide-directed switching to C epsilon. Mol Cell Biol 10( 4) : 1672– 1679.[PubMed]
116. Esser C,, Radbruch A . 1989. Rapid induction of transcription of unrearranged S gamma 1 switch regions in activated murine B cells by interleukin 4. EMBO J 8( 2) : 483– 488.[PubMed]
117. Shinkura R,, Tian M,, Smith M,, Chua K,, Fujiwara Y,, Alt FW . 2003. The influence of transcriptional orientation on endogenous switch region function. Nat Immunol 4( 5) : 435– 441.[PubMed] [CrossRef]
118. Radbruch A,, Sablitzky F . 1983. Deletion of Cmu genes in mouse B lymphocytes upon stimulation with LPS. EMBO J 2( 11) : 1929– 1935.[PubMed]
119. Radbruch A,, Muller W,, Rajewsky K . 1986. Class switch recombination is IgG1 specific on active and inactive IgH loci of IgG1-secreting B-cell blasts. Proc Natl Acad Sci USA 83( 11) : 3954– 3957.[PubMed] [CrossRef]
120. Jung S,, Rajewsky K,, Radbruch A . 1993. Shutdown of class switch recombination by deletion of a switch region control element. Science 259( 5097) : 984– 987.[PubMed] [CrossRef]
121. Zhang J,, Bottaro A,, Li S,, Stewart V,, Alt FW . 1993. A selective defect in IgG2b switching as a result of targeted mutation of the I gamma 2b promoter and exon. EMBO J 12( 9) : 3529– 3537.[PubMed]
122. Bottaro A,, Lansford R,, Xu L,, Zhang J,, Rothman P,, Alt FW . 1994. S region transcription per se promotes basal IgE class switch recombination but additional factors regulate the efficiency of the process. EMBO J 13( 3) : 665– 674.[PubMed]
123. Seidl KJ,, Bottaro A,, Vo A,, Zhang J,, Davidson L,, Alt FW . 1998. An expressed neo(r) cassette provides required functions of the 1gamma2b exon for class switching. Int Immunol 10( 11) : 1683– 1692.[PubMed] [CrossRef]
124. Lorenz M,, Jung S,, Radbruch A . 1995. Switch transcripts in immunoglobulin class switching. Science 267( 5205) : 1825– 1828.[PubMed] [CrossRef]
125. Qiu G,, Harriman GR,, Stavnezer J . 1999. Ialpha exon-replacement mice synthesize a spliced HPRT-C(alpha) transcript which may explain their ability to switch to IgA. Inhibition of switching to IgG in these mice. Int Immunol 11( 1) : 37– 46.[PubMed] [CrossRef]
126. Cogne M,, Lansford R,, Bottaro A,, Zhang J,, Gorman J,, Young F,, Cheng HL,, Alt FW . 1994. A class switch control region at the 3′ end of the immunoglobulin heavy chain locus. Cell 77( 5) : 737– 747.[PubMed] [CrossRef]
127. Seidl KJ,, Manis JP,, Bottaro A,, Zhang J,, Davidson L,, Kisselgof A,, Oettgen H,, Alt FW . 1999. Position-dependent inhibition of class-switch recombination by PGK-neor cassettes inserted into the immunoglobulin heavy chain constant region locus. Proc Natl Acad Sci USA 96( 6) : 3000– 3005.[PubMed] [CrossRef]
128. Wuerffel R,, Wang L,, Grigera F,, Manis J,, Selsing E,, Perlot T,, Alt FW,, Cogne M,, Pinaud E,, Kenter AL . 2007. S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity 27( 5) : 711– 722.[PubMed] [CrossRef]
129. Yan Y,, Pieretti J,, Ju Z,, Wei S,, Christin JR,, Bah F,, Birshtein BK,, Eckhardt LA . 2011. Homologous elements hs3a and hs3b in the 3′ regulatory region of the murine immunoglobulin heavy chain (Igh) locus are both dispensable for class-switch recombination. J Biol Chem 286( 31) : 27123– 27131.[PubMed] [CrossRef]
130. Han L,, Masani S,, Yu K . 2011. Overlapping activation-induced cytidine deaminase hotspot motifs in Ig class-switch recombination. Proc Natl Acad Sci USA 108( 28) : 11584– 11589.[PubMed] [CrossRef]
131. Zarrin AA,, Alt FW,, Chaudhuri J,, Stokes N,, Kaushal D,, Du Pasquier L,, Tian M . 2004. An evolutionarily conserved target motif for immunoglobulin class-switch recombination. Nat Immunol 5( 12) : 1275– 1281.[PubMed] [CrossRef]
132. Mussmann R,, Courtet M,, Schwager J,, Du Pasquier L . 1997. Microsites for immunoglobulin switch recombination breakpoints from Xenopus to mammals. Eur J Immunol 27( 10) : 2610– 2619.[PubMed] [CrossRef]
133. Yu K,, Chedin F,, Hsieh CL,, Wilson TE,, Lieber MR . 2003. R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nat Immunol 4( 5) : 442– 451.[PubMed] [CrossRef]
134. Reaban ME,, Griffin JA . 1990. Induction of RNA-stabilized DNA conformers by transcription of an immunoglobulin switch region. Nature 348( 6299) : 342– 344.[PubMed] [CrossRef]
135. Daniels GA,, Lieber MR . 1995. RNA:DNA complex formation upon transcription of immunoglobulin switch regions: implications for the mechanism and regulation of class switch recombination. Nucleic Acids Res 23( 24) : 5006– 5011.[PubMed] [CrossRef]
136. Tian M,, Alt FW . 2000. Transcription-induced cleavage of immunoglobulin switch regions by nucleotide excision repair nucleases in vitro. J Biol Chem 275( 31) : 24163– 24172.[PubMed] [CrossRef]
137. Mizuta R,, Iwai K,, Shigeno M,, Mizuta M,, Uemura T,, Ushiki T,, Kitamura D . 2003. Molecular visualization of immunoglobulin switch region RNA/DNA complex by atomic force microscope. J Biol Chem 278( 7) : 4431– 4434.[PubMed] [CrossRef]
138. Roy D,, Yu K,, Lieber MR . 2008. Mechanism of R-loop formation at immunoglobulin class switch sequences. Mol Cell Biol 28( 1) : 50– 60.[PubMed] [CrossRef]
139. Rajagopal D,, Maul RW,, Ghosh A,, Chakraborty T,, Khamlichi AA,, Sen R,, Gearhart PJ . 2009. Immunoglobulin switch mu sequence causes RNA polymerase II accumulation and reduces dA hypermutation. J Exp Med 206( 6) : 1237– 1244.[PubMed] [CrossRef]
140. Wang L,, Wuerffel R,, Feldman S,, Khamlichi AA,, Kenter AL . 2009. S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination. J Exp Med 206( 8) : 1817– 1830.[PubMed] [CrossRef]
141. Vuong BQ,, Lee M,, Kabir S,, Irimia C,, Macchiarulo S,, McKnight GS,, Chaudhuri J . 2009. Specific recruitment of protein kinase A to the immunoglobulin locus regulates class-switch recombination. Nat Immunol 10( 4) : 420– 426.[PubMed] [CrossRef]
142. Yamane A,, Resch W,, Kuo N,, Kuchen S,, Li Z,, Sun HW,, Robbiani DF,, McBride K,, Nussenzweig MC,, Casellas R . 2011. Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes. Nat Immunol 12( 1) : 62– 69.[PubMed] [CrossRef]
143. Basu U,, Chaudhuri J,, Alpert C,, Dutt S,, Ranganath S,, Li G,, Schrum JP,, Manis JP,, Alt FW . 2005. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 438( 7067) : 508– 511.[PubMed] [CrossRef]
144. Vuong BQ,, Herrick-Reynolds K,, Vaidyanathan B,, Pucella JN,, Ucher AJ,, Donghia NM,, Gu X,, Nicolas L,, Nowak U,, Rahman N,, Strout MP,, Mills KD,, Stavnezer J,, Chaudhuri J . 2013. A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination. Nat Immunol 14( 11) : 1183– 1189.[PubMed] [CrossRef]
145. Keim C,, Kazadi D,, Rothschild G,, Basu U . 2013. Regulation of AID, the B-cell genome mutator. Genes Dev 27( 1) : 1– 17.[PubMed] [CrossRef]
146. Cannon JP,, Haire RN,, Rast JP,, Litman GW . 2004. The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms. Immunol Rev 200 : 12– 22.[PubMed] [CrossRef]
147. Stavnezer J,, Amemiya CT . 2004. Evolution of isotype switching. Semin Immunol 16( 4) : 257– 275.[PubMed] [CrossRef]
148. Larson ED,, Duquette ML,, Cummings WJ,, Streiff RJ,, Maizels N . 2005. MutSalpha binds to and promotes synapsis of transcriptionally activated immunoglobulin switch regions. Curr Biol 15( 5) : 470– 474.[PubMed] [CrossRef]
149. Lundqvist ML,, Middleton DL,, Hazard S,, Warr GW . 2001. The immunoglobulin heavy chain locus of the duck. Genomic organization and expression of D, J, and C region genes. J Biol Chem 276( 50) : 46729– 46736.[PubMed] [CrossRef]
150. Zhang Y,, McCord RP,, Ho YJ,, Lajoie BR,, Hildebrand DG,, Simon AC,, Becker MS,, Alt FW,, Dekker J . 2012. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148( 5) : 908– 921.[PubMed] [CrossRef]
151. 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. Proc Natl Acad Sci USA 99( 15) : 9984– 9989.[PubMed] [CrossRef]
152. Zarrin AA,, Del Vecchio C,, Tseng E,, Gleason M,, Zarin P,, Tian M,, Alt FW . 2007. Antibody class switching mediated by yeast endonuclease-generated DNA breaks. Science 315( 5810) : 377– 381.[PubMed] [CrossRef]
153. Gostissa M,, Schwer B,, Chang A,, Dong J,, Meyers RM,, Marecki GT,, Choi VW,, Chiarle R,, Zarrin AA,, Alt FW . 2014. IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances. Proc Natl Acad Sci USA 111( 7) : 2644– 2649.[PubMed] [CrossRef]
154. Dixon JR,, Selvaraj S,, Yue F,, Kim A,, Li Y,, Shen Y,, Hu M,, Liu JS,, Ren B . 2012. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485( 7398) : 376– 380.[PubMed] [CrossRef]
155. Nagano T,, Lubling Y,, Stevens TJ,, Schoenfelder S,, Yaffe E,, Dean W,, Laue ED,, Tanay A,, Fraser P . 2013. Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 502( 7469) : 59– 64.[PubMed] [CrossRef]
156. Naumova N,, Imakaev M,, Fudenberg G,, Zhan Y,, Lajoie BR,, Mirny LA,, Dekker J . 2013. Organization of the mitotic chromosome. Science 342( 6161) : 948– 953.[PubMed] [CrossRef]
157. Nora EP,, Lajoie BR,, Schulz EG,, Giorgetti L,, Okamoto I,, Servant N,, Piolot T,, van Berkum NL,, Meisig J,, Sedat J,, Gribnau J,, Barillot E,, Bluthgen N,, Dekker J,, Heard E . 2012. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485( 7398) : 381– 385.[PubMed] [CrossRef]
158. Kenter AL,, Feldman S,, Wuerffel R,, Achour I,, Wang L,, Kumar S . 2012. Three-dimensional architecture of the IgH locus facilitates class switch recombination. Ann N Y Acad Sci 1267 : 86– 94.[PubMed] [CrossRef]
159. Bassing CH,, Alt FW . 2004. H2AX may function as an anchor to hold broken chromosomal DNA ends in close proximity. Cell Cycle 3( 2) : 149– 153.[PubMed] [CrossRef]
160. Nussenzweig A,, Nussenzweig MC . 2010. Origin of chromosomal translocations in lymphoid cancer. Cell 141( 1) : 27– 38.[PubMed] [CrossRef]
161. Rogakou EP,, Boon C,, Redon C,, Bonner WM . 1999. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146( 5) : 905– 916.[PubMed] [CrossRef]
162. Franco S,, Gostissa M,, Zha S,, Lombard DB,, Murphy MM,, Zarrin AA,, Yan C,, Tepsuporn S,, Morales JC,, Adams MM,, Lou Z,, Bassing CH,, Manis JP,, Chen J,, Carpenter PB,, Alt FW . 2006. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell 21( 2) : 201– 214.[PubMed] [CrossRef]
163. Ramiro AR,, Jankovic M,, Callen E,, Difilippantonio S,, Chen HT,, McBride KM,, Eisenreich TR,, Chen J,, Dickins RA,, Lowe SW,, Nussenzweig A,, Nussenzweig MC . 2006. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 440( 7080) : 105– 109.[PubMed] [CrossRef]
164. Manis JP,, Morales JC,, Xia Z,, Kutok JL,, Alt FW,, Carpenter PB . 2004. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat Immunol 5( 5) : 481– 487.[PubMed] [CrossRef]
165. Ward IM,, Reina-San-Martin B,, Olaru A,, Minn K,, Tamada K,, Lau JS,, Cascalho M,, Chen L,, Nussenzweig A,, Livak F,, Nussenzweig MC,, Chen J . 2004. 53BP1 is required for class switch recombination. J Cell Biol 165( 4) : 459– 464.[PubMed] [CrossRef]
166. Bothmer A,, Robbiani DF,, Feldhahn N,, Gazumyan A,, Nussenzweig A,, Nussenzweig MC . 2010. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J Exp Med 207( 4) : 855– 865.[PubMed] [CrossRef]
167. Bothmer A,, Robbiani DF,, Di Virgilio M,, Bunting SF,, Klein IA,, Feldhahn N,, Barlow J,, Chen HT,, Bosque D,, Callen E,, Nussenzweig A,, Nussenzweig MC . 2011. Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1. Mol Cell 42( 3) : 319– 329.[PubMed] [CrossRef]
168. Difilippantonio S,, Gapud E,, Wong N,, Huang CY,, Mahowald G,, Chen HT,, Kruhlak MJ,, Callen E,, Livak F,, Nussenzweig MC,, Sleckman BP,, Nussenzweig A . 2008. 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature 456( 7221) : 529– 533.[PubMed] [CrossRef]
169. Chapman JR,, Barral P,, Vannier JB,, Borel V,, Steger M,, Tomas-Loba A,, Sartori AA,, Adams IR,, Batista FD,, Boulton SJ . 2013. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol Cell 49( 5) : 858– 871.[PubMed] [CrossRef]
170. Di Virgilio M,, Callen E,, Yamane A,, Zhang W,, Jankovic M,, Gitlin AD,, Feldhahn N,, Resch W,, Oliveira TY,, Chait BT,, Nussenzweig A,, Casellas R,, Robbiani DF,, Nussenzweig MC . 2013. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339( 6120) : 711– 715.[PubMed] [CrossRef]
171. Zimmermann M,, Lottersberger F,, Buonomo SB,, Sfeir A,, de Lange T . 2013. 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science 339( 6120) : 700– 704.[PubMed] [CrossRef]
172. Kumar V,, Alt FW,, Oksenych V . 2014. Functional overlaps between XLF and the ATM-dependent DNA double strand break response. DNA Repair 16 : 11– 22.[PubMed] [CrossRef]
173. Lieber MR . 2010. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79 : 181– 211.[PubMed] [CrossRef]
174. Boboila C,, Alt FW,, Schwer B . 2012. Classical and alternative end-joining pathways for repair of lymphocyte-specific and general DNA double-strand breaks. Adv Immunol 116 : 1– 49.[PubMed] [CrossRef]
175. Yan CT,, Boboila C,, Souza EK,, Franco S,, Hickernell TR,, Murphy M,, Gumaste S,, Geyer M,, Zarrin AA,, Manis JP,, Rajewsky K,, Alt FW . 2007. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449( 7161) : 478– 482.[PubMed] [CrossRef]
176. Stavnezer J,, Bjorkman A,, Du L,, Cagigi A,, Pan-Hammarstrom W . 2010. Mapping of switch recombination junctions, a tool for studying DNA repair pathways during immunoglobulin class switching. Adv Immunol 108 : 45– 109.[PubMed] [CrossRef]
177. Taccioli GE,, Rathbun G,, Oltz E,, Stamato T,, Jeggo PA,, Alt FW . 1993. Impairment of V(D)J recombination in double-strand break repair mutants. Science 260( 5105) : 207– 210.[PubMed] [CrossRef]
178. Meek K,, Gupta S,, Ramsden DA,, Lees-Miller SP . 2004. The DNA-dependent protein kinase: the director at the end. Immunol Rev 200 : 132– 141.[PubMed] [CrossRef]
179. Nussenzweig A,, Chen C,, da Costa Soares V,, Sanchez M,, Sokol K,, Nussenzweig MC,, Li GC . 1996. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 382( 6591) : 551– 555.[PubMed] [CrossRef]
180. Frank KM,, Sekiguchi JM,, Seidl KJ,, Swat W,, Rathbun GA,, Cheng HL,, Davidson L,, Kangaloo L,, Alt FW . 1998. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396( 6707) : 173– 177.[PubMed] [CrossRef]
181. Gao Y,, Sun Y,, Frank KM,, Dikkes P,, Fujiwara Y,, Seidl KJ,, Sekiguchi JM,, Rathbun GA,, Swat W,, Wang J,, Bronson RT,, Malynn BA,, Bryans M,, Zhu C,, Chaudhuri J,, Davidson L,, Ferrini R,, Stamato T,, Orkin SH,, Greenberg ME,, Alt FW . 1998. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95