Antibody Class Switch Recombination: Roles for Switch Sequences and Mismatch Repair Proteins

Aldrich, 2003, Impaired germinal center maturation in adenosine deaminase deficiency, J. Immunol., 171, 5562, 10.4049/jimmunol.171.10.5562 Alt, 1982, Immunoglobulin heavy‐chain expression and class switching in a murine leukaemia cell line, Nature, 296, 325, 10.1038/296325a0 Apel, 1990, Somatic mutations in antibodies expressed by germinal centre B cells early after primary immunization, Int. Immunol., 2, 813, 10.1093/intimm/2.9.813 Arakawa, 2002, Requirement of the activation‐induced deaminase (AID) gene for immunoglobulin gene conversion, Science, 295, 1301, 10.1126/science.1067308 Baker, 1995, Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis, Cell, 82, 309, 10.1016/0092-8674(95)90318-6 Bardwell, 2003, Cutting edge: The G‐U mismatch glycosylase methyl‐CpG binding domain 4 is dispensable for somatic hypermutation and class switch recombination, J. Immunol., 170, 1620, 10.4049/jimmunol.170.4.1620 Bardwell, 2004, Altered somatic hypermutation and reduced class‐switch recombination in exonuclease 1‐mutant mice, Nat. Immunol., 5, 224, 10.1038/ni1031 Beale, 2004, Comparison of the differential context‐dependence of DNA deamination by APOBEC enzymes: Correlation with mutation spectra in vivo, J. Mol. Biol., 337, 585, 10.1016/j.jmb.2004.01.046 Begum, 2004, Uracil DNA glycosylase activity is dispensable for immunoglobulin class switch, Science, 305, 1160, 10.1126/science.1098444 Bellacosa, 1999, MED1, a novel human methyl‐CpG‐binding endonuclease, interacts with DNA mismatch repair protein MLH1, Proc. Natl. Acad. Sci. USA, 96, 3969, 10.1073/pnas.96.7.3969 Bemark, 2000, Somatic hypermutation in the absence of DNA‐dependent protein kinase catalytic subunit (DNA‐PK(cs)) or recombination‐activating gene (RAG)1 activity, J. Exp. Med., 192, 1509, 10.1084/jem.192.10.1509 Bertocci, 1998, Probing immunoglobulin gene hypermutation with microsatellites suggests a nonreplicative short patch DNA synthesis process, Immunity, 9, 257, 10.1016/S1074-7613(00)80608-1 Betz, 1994, Elements regulating somatic hypermutation of an immunoglobulin kappa gene: Critical role for the intron enhancer/matrix attachment region, Cell, 77, 239, 10.1016/0092-8674(94)90316-6 Bosma, 2002, DNA‐dependent protein kinase activity is not required for immunoglobulin class switching, J. Exp. Med., 196, 1483, 10.1084/jem.20001871 Bottaro, 1994, S region transcription per se promotes basal IgE class switch recombination but additional factors regulate the efficiency of the process, EMBO J., 13, 665, 10.1002/j.1460-2075.1994.tb06305.x Bottaro, 1998, Deletion of the IgH intronic enhancer and associated matrix‐attachment regions decreases, but does not abolish, class switching at the mu locus, Int. Immunol., 10, 799, 10.1093/intimm/10.6.799 Bransteitter, 2003, Activation‐induced cytidine deaminase deaminates deoxycytidine on single‐stranded DNA but requires the action of RNase, Proc. Natl. Acad. Sci. USA, 100, 4102, 10.1073/pnas.0730835100 Cascalho, 1998, Mismatch repair co‐opted by hypermutation, Science, 279, 1207, 10.1126/science.279.5354.1207 Casellas, 1998, Ku80 is required for immunoglobulin isotype switching, EMBO J., 17, 2404, 10.1093/emboj/17.8.2404 Catalan, 2003, The block in immunoglobulin class switch recombination caused by activation‐induced cytidine deaminase deficiency occurs prior to the generation of DNA double strand breaks in switch mu region, J. Immunol., 171, 2504, 10.4049/jimmunol.171.5.2504 Chaudhuri, 2004, Replication protein A interacts with AID to promote deamination of somatic hypermutation targets, Nature, 430, 992, 10.1038/nature02821 Chaudhuri, 2003, Transcription‐targeted DNA deamination by the AID antibody diversification enzyme, Nature, 422, 726, 10.1038/nature01574 Chen, 2001, Variable deletion and duplication at recombination junction ends: Implication for staggered double‐strand cleavage in class‐switch recombination, Proc. Natl. Acad. Sci. USA, 98, 13860, 10.1073/pnas.241524898 Daniels, 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, 5006, 10.1093/nar/23.24.5006 Datta, 1996, Mitotic crossovers between diverged sequences are regulated by mismatch repair proteins in Saccaromyces cerevisiae, Mol. Cell. Biol., 16, 1085, 10.1128/MCB.16.3.1085 de Wind, 1995, Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer, Cell, 82, 321, 10.1016/0092-8674(95)90319-4 Delpy, 2003, Germ‐line transcription occurs on both the functional and the non‐functional alleles of immunoglobulin constant heavy chain genes, Eur. J. Immunol., 33, 2108, 10.1002/eji.200323969 Dempsey, 1999, G4 DNA binding by LR1 and its subunits, nucleolin and hnRNP D, A role for G‐G pairing in immunoglobulin switch recombination, J. Biol. Chem., 274, 1066, 10.1074/jbc.274.2.1066 Di Noia, 2002, Altering the pathway of immunoglobulin hypermutation by inhibiting uracil‐DNA glycosylase, Nature, 419, 43, 10.1038/nature00981 Dickerson, 2003, AID mediates hypermutation by deaminating single stranded DNA, J. Exp. Med., 197, 1291, 10.1084/jem.20030481 Doi, 2003, De novo protein synthesis is required for the activation‐induced cytidine deaminase function in class‐switch recombination, Proc. Natl. Acad. Sci. USA, 100, 2634, 10.1073/pnas.0437710100 Dunnick, 1993, DNA sequences at immunoglobulin switch region recombination sites, Nucleic Acids Res., 21, 365, 10.1093/nar/21.3.365 Dzantiev, 2004, A defined human system that supports bidirectional mismatch‐provoked excision, Mol. Cell, 15, 31, 10.1016/j.molcel.2004.06.016 Edelmann, 1996, Meiotic pachytene arrest in MLH1‐deficient mice, Cell, 85, 1125, 10.1016/S0092-8674(00)81312-4 Ehrenstein, 1999, Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class‐switch recombination: Parallels with somatic hypermutation, EMBO J., 18, 3484, 10.1093/emboj/18.12.3484 Ehrenstein, 2001, Switch junction sequences in PMS2‐deficient mice reveal a microhomology‐mediated mechanism of Ig class switch recombination, Proc. Natl. Acad. Sci. USA, 98, 14553, 10.1073/pnas.241525998 Evans, 2000, Roles for mismatch repair factors in regulating genetic recombination, Mol. Cell. Biol., 20, 7839, 10.1128/MCB.20.21.7839-7844.2000 Faili, 2004, DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination, J. Exp. Med., 199, 265, 10.1084/jem.20031831 Flores‐Rozas, 1998, The Saccharomyces cerevisiae MLH3 gene functions in MSH3‐dependent suppression of frameshift mutations, Proc. Natl. Acad. Sci. USA, 95, 12404, 10.1073/pnas.95.21.12404 Frey, 1998, Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process, Immunity, 9, 127, 10.1016/S1074-7613(00)80594-4 Fukita, 1998, Somatic hypermutation in the heavy chain locus correlates with transcription, Immunity, 9, 105, 10.1016/S1074-7613(00)80592-0 Fukumura, 2000, Signal joint formation is also impaired in DNA‐dependent protein kinase catalytic subunit knockout cells, J. Immunol., 165, 3883, 10.4049/jimmunol.165.7.3883 Gao, 1998, A targeted DNA‐PKcs‐null mutation reveals DNA‐PK‐independent functions for KU in V(D)J recombination, Immunity, 9, 367, 10.1016/S1074-7613(00)80619-6 Gu, 1997, Growth retardation and leaky SCID phenotype of Ku70‐deficient mice, Immunity, 7, 653, 10.1016/S1074-7613(00)80386-6 Harris, 2002, AID is essential for immunoglobulin V gene conversion in a cultured B cell line, Curr. Biol., 12, 435, 10.1016/S0960-9822(02)00717-0 Honjo, 1978, Organization of immunoglobulin heavy chain genes and allelic deletion model, Proc. Natl. Acad. Sci. USA, 75, 2140, 10.1073/pnas.75.5.2140 Honjo, 2002, Molecular mechanism of class switch recombination: linkage with somatic hypermutation, Annu. Rev. Immunol., 20, 165, 10.1146/annurev.immunol.20.090501.112049 Hummel, 1987, Switch region content of hybridomas: The two spleen cell Igh loci tend to rearrange to the same isotype, J. Immunol., 138, 3539, 10.4049/jimmunol.138.10.3539 Ito, 2004, Activation‐induced cytidine deaminase shuttles between nucleus and cytoplasm like apolipoprotein B mRNA editing catalytic polypeptide 1, Proc. Natl. Acad. Sci. USA, 101, 1975, 10.1073/pnas.0307335101 Iwasato, 1990, Circular DNA is excised by immunoglobulin class switch recombination, Cell, 62, 143, 10.1016/0092-8674(90)90248-D Jacobs, 1998, Hypermutation of immunoglobulin genes in memory B cells of DNA repair‐deficient mice, J. Exp. Med., 187, 1735, 10.1084/jem.187.11.1735 Jacobs, 1999, Tuning somatic hypermutation by transcription, Curr. Top Microbiol. Immunol., 246, 149, 10.1007/978-3-642-60162-0_19 Jung, 1993, Shutdown of class switch recombination by deletion of as witch region control element, Science, 259, 984, 10.1126/science.8438159 Kataoka, 1981, Repetitive sequences in class‐switch recombination regions of immunoglobulin heavy chain genes, Cell, 23, 357, 10.1016/0092-8674(81)90131-8 Kearney, 1976, B cell differentiation induced by lipopolysaccharide. IV. Development of immunoglobulin class restriction in precursors of IgG‐synthesizing cells, J. Immunol., 117, 1567, 10.4049/jimmunol.117.5_Part_1.1567 Kearney, 1975, B lymphocyte differentiation induced by lipopolysaccharide. I. Generation of cells synthesizing four major immunoglobulin classes, J. Immunol., 115, 671, 10.4049/jimmunol.115.3.671 Kenter, 2004, Mapping of a functional recombination motif that defines isotype specificity for mu–>gamma3 switch recombination implicates NF‐kappaB p50 as the isotype‐specific switching factor, J. Exp. Med., 199, 617, 10.1084/jem.20031935 Khamlichi, 2004, Immunoglobulin class‐switch recombination in mice devoid of any S mu tandem repeat, Blood, 103, 3828, 10.1182/blood-2003-10-3470 Kim, 1999, Different mismatch repair deficiencies all have the same effects on somatic hypermutation: Intact primary mechanism accompanied by secondary modifications, J. Exp. Med., 190, 21, 10.1084/jem.190.1.21 Kinoshita, 1998, Target specificity of immunoglobulin class switch recombination is not determined by nucleotide sequences of S regions, Immunity, 9, 849, 10.1016/S1074-7613(00)80650-0 Kitao, 2000, Class switch recombination of the chicken IgH chain genes: Implications for the primordial switch region repeats, Int. Immunol., 12, 959, 10.1093/intimm/12.7.959 Kolodner, 1999, Eukaryotic DNA mismatch repair, Curr. Opin. Genet. Dev., 9, 89, 10.1016/S0959-437X(99)80013-6 Krokan, 2002, Uracil in DNA–occurrence, consequences and repair, Oncogene, 21, 8935, 10.1038/sj.onc.1205996 Lahdesmaki, 2004, Delineation of the role of the Mre11 complex in class switch recombination, J. Biol. Chem., 279, 16479, 10.1074/jbc.M312796200 Lee, 1998, Separation and identification of microcystins in cyanobacteria by frit‐fast atom bombardment liquid chromatography/mass spectrometry, Current Biology, 8, 227, 10.1016/S0960-9822(98)70087-9 Lee, 2001, Quantitative regulation of class switch recombination by switch region transcription, J. Exp. Med., 194, 365, 10.1084/jem.194.3.365 Lennon, 1985, C mu‐containing transcripts initiate heterogeneously within the IgH enhancer region and contain a novel 5′‐nontranslatable exon, Nature, 318, 475, 10.1038/318475a0 Li, 2004, Examination of Msh6‐ and Msh3‐deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification, J. Exp. Med., 200, 47, 10.1084/jem.20040355 Lieber, 1988, The defect in murine severe combined immune deficiency: Joining of signal sequences but not coding segments in V(D)J recombination, Cell, 55, 7, 10.1016/0092-8674(88)90004-9 Lieber, 2003, Mechanism and regulation of human non‐homologous DNA end‐joining, Nat. Rev. Mol. Cell. Biol., 4, 712, 10.1038/nrm1202 Lipkin, 2002, Meiotic arrest and aneuploidy in MLH3‐deficient mice, Nat. Genet., 31, 385, 10.1038/ng931 Lorenz, 1995, Switch transcripts in immunoglobulin class switching, Science, 267, 1825, 10.1126/science.7892607 Luby, 2001, The mu switch region tandem repeats are important, but not required, for antibody class switch recombination, J. Exp. Med., 193, 159, 10.1084/jem.193.2.159 Luby, 2001, Sequences associated with the mouse Smu switch region are important for immunoglobulin heavy chain transgene expression in B cell development, Eur. J. Immunol., 31, 2866, 10.1002/1521-4141(2001010)31:10<2866::AID-IMMU2866>3.0.CO;2-0 Lutzker, 1988, Mitogen‐ and IL‐4‐regulated expression of germ‐line Ig gamma 2b transcripts: Evidence for directed heavy chain class switching, Cell, 53, 177, 10.1016/0092-8674(88)90379-0 Ma, 2002, Hairpin opening and overhang processing by an Artemis/DNA‐dependent protein kinase complex in nonhomologous end joining and V(D)J recombination, Cell, 108, 781, 10.1016/S0092-8674(02)00671-2 Malynn, 1988, The scid defect affects the final step of the immunoglobulin VDJ recombinase mechanism, Cell, 54, 453, 10.1016/0092-8674(88)90066-9 Manis, 2002, IgH class switch recombination to IgG1 in DNA‐PKcs‐deficient B cells, Immunity, 16, 607, 10.1016/S1074-7613(02)00306-0 Manis, 1998, Ku70 is required for late B cell development and immunoglobulin heavy chain class switching, J. Exp. Med., 187, 2081, 10.1084/jem.187.12.2081 Manis, 2004, 53BP1 links DNA damage‐response pathways to immunoglobulin heavy chain class‐switch recombination, Nat. Immunol., 5, 481, 10.1038/ni1067 Mantovani, 1993, Human rheumatoid B‐1a (CD5+ B) cells make somatically hypermutated high affinity IgM rheumatoid factors, J. Immunol., 151, 473, 10.4049/jimmunol.151.1.473 Martin, 2002, Activation‐induced cytidine deaminase turns on somatic hypermutation in hybridomas, Nature, 415, 802, 10.1038/nature714 Martin, 2002, AID and mismatch repair in antibody diversification, Nat. Rev. Immunol., 2, 605, 10.1038/nri858 Martomo, 2004, A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination, J. Exp. Med., 200, 61, 10.1084/jem.20040691 Matic, 1995, Interspecies gene exchange in bacteria: The role of SOS and mismatch repair systems in evolution of species, Cell, 80, 507, 10.1016/0092-8674(95)90501-4 Matsuoka, 1990, Switch circular DNA formed in cytokine‐treated mouse splenocytes: Evidence for intramolecular DNA deletion in immunoglobulin class switching, Cell, 62, 135, 10.1016/0092-8674(90)90247-C Min, 2003, The Smu tandem repeat region is critical for Ig isotype switching in the absence of Msh2, Immunity, 19, 515, 10.1016/S1074-7613(03)00262-0 Mizuta, 2003, Molecular visualization of immunoglobulin switch region RNA/DNA complex by atomic force microscope, J. Biol. Chem., 278, 4431, 10.1074/jbc.M209262200 Muramatsu, 2000, Class switch recombination and hypermutation require activation‐induced cytidine deaminase (AID), a potential RNA editing enzyme, Cell, 102, 553, 10.1016/S0092-8674(00)00078-7 Muramatsu, 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, 18470, 10.1074/jbc.274.26.18470 Mussmann, 1997, Microsites for immunoglobulin switch recombination breakpoints from Xenopus to mammals, Eur. J. Immunol., 27, 2610, 10.1002/eji.1830271021 Nagaoka, 2002, Activation‐induced deaminase (AID)‐directed hypermutation in the immunoglobulin Smu region: implication of AID involvement in a common step of class switch recombination and somatic hypermutation, J. Exp. Med., 195, 529, 10.1084/jem.20012144 Nambu, 2003, Transcription‐coupled events associating with immunoglobulin switch region chromatin, Science, 302, 2137, 10.1126/science.1092481 Okazaki, 2002, The AID enzyme induces class switch recombination in fibroblasts, Nature, 416, 340, 10.1038/nature727 Ono, 2000, Identification of a stimulus‐dependent DNase I hypersensitive site between the Ialpha and Calpha exons during immunoglobulin heavy chain class switch recombination, FEBS Lett., 467, 268, 10.1016/S0014-5793(00)01151-0 Ouyang, 1997, Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo, J. Exp. Med., 186, 921, 10.1084/jem.186.6.921 Pan‐Hammarstrom, 2003, ATM is not required in somatic hypermutation of VH, but is involved in the introduction of mutations in the switch mu region, J. Immunol., 170, 3707, 10.4049/jimmunol.170.7.3707 Pan‐Hammarstrom, 2004, Lack of association between human switch recombination breakpoints and the secondary structure of targeted DNA regions, J. Immunol., 172, 2727, 10.4049/jimmunol.172.5.2727 Peters, 1996, Somatic hypermutation of immunoglobulin genes is linked to transcription initiation, Immunity, 4, 57, 10.1016/S1074-7613(00)80298-8 Petersen, 2001, AID is required to initiate Nbs1/gamma‐H2AX focus formation and mutations at sites of class switching, Nature, 414, 660, 10.1038/414660a Petersen‐Mahrt, 2002, AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification, Nature, 418, 99, 10.1038/nature00862 Pham, 2003, Processive AID‐catalysed cytosine deamination on single‐stranded DNA simulates somatic hypermutation, Nature, 424, 103, 10.1038/nature01760 Phung, 1999, Hypermutation in Ig V genes from mice deficient in the MLH1 mismatch repair protein, J. Immunol., 162, 3121, 10.4049/jimmunol.162.6.3121 Phung, 1998, Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein, J. Exp. Med., 187, 1745, 10.1084/jem.187.11.1745 Rada, 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, 163, 10.1016/j.molcel.2004.10.011 Rada, 1998, Hot spot focusing of somatic hypermutation in MSH2‐deficient mice suggests two stages of mutational targeting, Immunity, 9, 135, 10.1016/S1074-7613(00)80595-6 Rada, 2002, Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG‐deficient mice, Curr. Biol., 12, 1748, 10.1016/S0960-9822(02)01215-0 Radbruch, 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, 3954, 10.1073/pnas.83.11.3954 Ramiro, 2003, Transcription enhances AID‐mediated cytidine deamination by exposing single‐stranded DNA on the nontemplate strand, Nat. Immunol., 4, 452, 10.1038/ni920 Reaban, 1990, Induction of RNA‐stabilized DNA conformers by transcription of an immunoglobulin switch region, Nature, 348, 342, 10.1038/348342a0 Reaban, 1994, Transcription induces the formation of a stable RNA.DNA hybrid in the immunoglobulin alpha switch region, J. Biol. Chem., 269, 21850, 10.1016/S0021-9258(17)31881-1 Reina‐San‐Martin, 2003, H2AX is required for recombination between immunoglobulin switch regions but not for intra‐switch region recombination or somatic hypermutation, J. Exp. Med., 197, 1767, 10.1084/jem.20030569 Reitmair, 1995, MSH2 deficient mice are viable and susceptible to lymphoid tumours, Nat. Genet., 11, 64, 10.1038/ng0995-64 Revy, 2000, Activation‐induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper‐IgM syndrome (HIGM2), Cell, 102, 565, 10.1016/S0092-8674(00)00079-9 Rolink, 1996, The SCID but not the RAG‐2 gene product is required for S mu‐S epsilon heavy chain class switching, Immunity, 5, 319, 10.1016/S1074-7613(00)80258-7 Rooney, 2004, The role of the non‐homologous end‐joining pathway in lymphocyte development, Immunol. Rev., 200, 115, 10.1111/j.0105-2896.2004.00165.x Rothman, 1988, Mitogen plus interleukin 4 induction of C epsilon transcripts in B lymphoid cells, J. Exp. Med., 168, 2385, 10.1084/jem.168.6.2385 Rush, 2004, Staggered AID‐dependent DNA double strand breaks are the predominant DNA lesions targeted to S mu in Ig class switch recombination, Int. Immunol., 16, 549, 10.1093/intimm/dxh057 Sale, 2001, Ablation of XRCC2/3 transforms immunoglobulin V gene conversion into somatic hypermutation, Nature, 412, 921, 10.1038/35091100 Schmutte, 1998, Human exonuclease I interacts with the mismatch repair protein hMSH2, Cancer Res., 58, 4537 Schofield, 2003, DNA mismatch repair: Molecular mechanisms and biological function, Annu. Rev. Microbiol., 57, 579, 10.1146/annurev.micro.57.030502.090847 Schrader, 1999, Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes, J. Exp. Med., 190, 323, 10.1084/jem.190.3.323 Schrader, 2003, Mutations occur in the Ig Smu region but rarely in Sgamma regions prior to class switch recombination, EMBO J., 22, 5893, 10.1093/emboj/cdg550 Schrader, 2002, Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions, J. Exp. Med., 195, 367, 10.1084/jem.20011877 Schrader, 2003, Mlh1 can function in antibody class switch recombination independently of Msh2, J. Exp. Med., 197, 1377, 10.1084/jem.20022190 Schultz, 1990, Patterns and extent of isotype‐specificity in the murine H chain switch DNA rearrangement, J. Immunol., 144, 363, 10.4049/jimmunol.144.1.363 Seidl, 1998, An expressed neo(r) cassette provides required functions of the 1gamma2b exon for class switching, Int. Immunol., 10, 1683, 10.1093/intimm/10.11.1683 Shinkura, 2004, Separate domains of AID are required for somatic hypermutation and class‐switch recombination, Nat. Immunol., 5, 707, 10.1038/ni1086 Shinkura, 2003, The influence of transcriptional orientation on endogenous switch region function, Nat. Immunol., 4, 435, 10.1038/ni918 Smith, 1996, Base‐modification mRNA editing through deamination–the good, the bad and the unregulated, Trends Genet., 12, 418, 10.1016/0168-9525(96)10042-1 Sohn, 1993, Somatic hypermutation of an immunoglobulin mu heavy chain transgene, J. Exp. Med., 177, 493, 10.1084/jem.177.2.493 Stavnezer, 1996, 79, 10.1016/S0065-2776(08)60866-4 Stavnezer, 1988, Immunoglobulin heavy‐chain switching may be directed by prior induction of transcripts from constant‐region genes, Proc. Natl. Acad. Sci. USA, 85, 7704, 10.1073/pnas.85.20.7704 Stavnezer‐Nordgren, 1986, Specificity of immunoglobulin heavy chain switch correlates with activity of germline heavy chain genes prior to switching, EMBO J., 5, 95, 10.1002/j.1460-2075.1986.tb04182.x Storb, 1998, Somatic hypermutation of immunoglobulin genes is linked to transcription, Curr. Top Microbiol. Immunol., 229, 11, 10.1007/978-3-642-71984-4_2 Sugawara, 1997, Role of Saccharomyces cerevisiae Msh2 and Msh3 repair proteins in double‐strand break‐induced recombination, Proc. Natl. Acad. Sci. USA, 94, 9214, 10.1073/pnas.94.17.9214 Tashiro, 2001, Palindromic but not G‐rich sequences are targets of class switch recombination, Int. Immunol., 13, 495, 10.1093/intimm/13.4.495 Tian, 2000, Transcription‐induced cleavage of immunoglobulin switch regions by nucleotide excision repair nucleases in vitro, J. Biol. Chem., 275, 24163, 10.1074/jbc.M003343200 Tian, 2004, Deficiency in the nuclease activity of xeroderma pigmentosum G in mice leads to hypersensitivity to UV irradiation, Mol. Cell. Biol., 24, 2237, 10.1128/MCB.24.6.2237-2242.2004 Tian, 2004, Growth retardation, early death, and DNA repair defects in mice deficient for the nucleotide excision repair enzyme XPF, Mol. Cell. Biol., 24, 1200, 10.1128/MCB.24.3.1200-1205.2004 Tishkoff, 1997, Identification and characterization of Saccharomyces cerevisiae EXO1, a gene encoding an exonuclease that interacts with MSH2, Proc. Natl. Acad. Sci. USA, 94, 7487, 10.1073/pnas.94.14.7487 Tran, 2001, Interactions of Exo1p with components of MutLalpha in Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. USA, 98, 9760, 10.1073/pnas.161175998 Vogel, 1999, Deletion of Ku86 causes early onset of senescence in mice, Proc. Natl. Acad. Sci. USA, 96, 10770, 10.1073/pnas.96.19.10770 von Schwedler, 1990, Circular DNA is a product of the immunoglobulin class switch rearrangement, Nature, 345, 452, 10.1038/345452a0 Vora, 1999, Severe attenuation of the B cell immune response in Msh2‐deficient mice, J. Exp. Med., 189, 471, 10.1084/jem.189.3.471 Wiesendanger, 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, 579, 10.1084/jem.191.3.579 Winter, 1998, Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2, Proc. Natl. Acad. Sci. USA, 95, 6953, 10.1073/pnas.95.12.6953 Winter, 1987, Directed Ig class switch recombination in activated murine B cells, EMBO J., 6, 1663, 10.1002/j.1460-2075.1987.tb02415.x Woo, 2003, Induction of somatic hypermutation is associated with modifications in immunoglobulin variable region chromatin, Immunity, 19, 479, 10.1016/S1074-7613(03)00261-9 Wuerffel, 1997, Ig Sgamma3 DNA‐specific double strand breaks are induced in mitogen‐activated B cells and are implicated in switch recombination, J. Immunol., 159, 4139, 10.4049/jimmunol.159.9.4139 Yoshikawa, 2002, AID enzyme‐induced hypermutation in an actively transcribed gene in fibroblasts, Science, 296, 2033, 10.1126/science.1071556 Yu, 2003, R‐loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells, Nat. Immunol., 4, 442, 10.1038/ni919 Yu, 2004, DNA substrate length and surrounding sequence affect the activation‐induced deaminase activity at cytidine, J. Biol. Chem., 279, 6496, 10.1074/jbc.M311616200 Yu, 2003, Nucleic acid structures and enzymes in the immunoglobulin class switch recombination mechanism, DNA Repair (Amst), 2, 1163, 10.1016/j.dnarep.2003.08.010 Zarrin, 2004, An evolutionarily conserved target motif for immunoglobulin class‐switch recombination, Nat. Immunol., 5, 1275, 10.1038/ni1137 Zhang, 1993, A selective defect in IgG2b switching as a result of targeted mutation of the I gamma 2b promoter and exon, EMBO J., 12, 3529, 10.1002/j.1460-2075.1993.tb06027.x Zhu, 1996, Ku86‐deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates, Cell, 86, 379, 10.1016/S0092-8674(00)80111-7