Genomes and Genes
immunoglobulin switch region
Summary: A site located in the INTRONS at the 5' end of each constant region segment of a immunoglobulin heavy-chain gene where recombination (or rearrangement) occur during IMMUNOGLOBULIN CLASS SWITCHING. Ig switch regions are found on genes encoding all five classes (IMMUNOGLOBULIN ISOTYPES) of IMMUNOGLOBULIN HEAVY CHAINS.
- Kracker S, Bergmann Y, Demuth I, Frappart P, Hildebrand G, Christine R, et al. Nibrin functions in Ig class-switch recombination. Proc Natl Acad Sci U S A. 2005;102:1584-9 pubmed
- Reina San Martin B, Nussenzweig M, Nussenzweig A, Difilippantonio S. Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc Natl Acad Sci U S A. 2005;102:1590-5 pubmed..Our findings reveal that Nbs1 is critical for efficient Ig CSR and maintenance of the integrity of chromosomal structure and number. ..
- Luby T, Schrader C, Stavnezer J, Selsing E. The mu switch region tandem repeats are important, but not required, for antibody class switch recombination. J Exp Med. 2001;193:159-68 pubmed..The maintenance of the highly repeated S(mu) element during evolution appears to reflect selection for a highly efficient switching process rather than selection for a required sequence element. ..
- Lee C, Kinoshita K, Arudchandran A, Cerritelli S, Crouch R, Honjo T. Quantitative regulation of class switch recombination by switch region transcription. J Exp Med. 2001;194:365-74 pubmed..Such structures may be recognition targets of a putative class switch recombinase. ..
- Chen X, Kinoshita K, Honjo T. Variable deletion and duplication at recombination junction ends: implication for staggered double-strand cleavage in class-switch recombination. Proc Natl Acad Sci U S A. 2001;98:13860-5 pubmed..These findings suggest that single-strand tails of staggered cleavage may be repaired by error-prone DNA synthesis. ..
- Lähdesmäki A, Taylor A, Chrzanowska K, Pan Hammarstrom Q. Delineation of the role of the Mre11 complex in class switch recombination. J Biol Chem. 2004;279:16479-87 pubmed
- Zarrin A, Tian M, Wang J, Borjeson T, Alt F. Influence of switch region length on immunoglobulin class switch recombination. Proc Natl Acad Sci U S A. 2005;102:2466-70 pubmed..Moreover, these results also will allow the development of a systematic system to test the function of various S-region motifs by replacing endogenous S regions with synthetic S regions controlled for size effects. ..
- Pan Q, Petit Frère C, Lähdesmäki A, Gregorek H, Chrzanowska K, Hammarstrom L. Alternative end joining during switch recombination in patients with ataxia-telangiectasia. Eur J Immunol. 2002;32:1300-8 pubmed..Thus, the general pathway involved in DNA repair also has a major influence on the immunoglobulin isotype switching process. ..
- Longerich S, Basu U, Alt F, Storb U. AID in somatic hypermutation and class switch recombination. Curr Opin Immunol. 2006;18:164-74 pubmed
- Huang F, Yu K, Hsieh C, Lieber M. Downstream boundary of chromosomal R-loops at murine switch regions: implications for the mechanism of class switch recombination. Proc Natl Acad Sci U S A. 2006;103:5030-5 pubmed..The implications of these findings are discussed in the context of models for the targeting of class switch recombination. ..
- Zarrin A, Del Vecchio C, Tseng E, Gleason M, Zarin P, Tian M, et al. Antibody class switching mediated by yeast endonuclease-generated DNA breaks. Science. 2007;315:377-81 pubmed..We propose that CSR evolved to exploit a general DNA repair process that promotes joining of widely separated DSBs within a chromosome. ..
- Mills F, Brooker J, Camerini Otero R. Sequences of human immunoglobulin switch regions: implications for recombination and transcription. Nucleic Acids Res. 1990;18:7305-16 pubmed..The epsilon and gamma 4 conserved segments contain potential Interferon Stimulable Response Elements (ISRE's) that are identical between human epsilon and gamma 4. ..
- Shanmugam A, Shi M, Yauch L, Stavnezer J, Kenter A. Evidence for class-specific factors in immunoglobulin isotype switching. J Exp Med. 2000;191:1365-80 pubmed..Finally, we provide evidence for two distinct switching activities which independently mediate mu-->alpha and mu-->gamma3 SR. ..
- Pan Hammarstrom Q, Dai S, Zhao Y, van Dijk Härd I, Gatti R, Børresen Dale A, et al. ATM is not required in somatic hypermutation of VH, but is involved in the introduction of mutations in the switch mu region. J Immunol. 2003;170:3707-16 pubmed..ATM may thus be one of the factors that is not shared by the CSR and SHM processes. ..
- Kenter A. Class switch recombination: an emerging mechanism. Curr Top Microbiol Immunol. 2005;290:171-99 pubmed..A global picture of the mechanism of CSR is emerging and is providing new insights toward understanding the genetic events that underlie B cell cancers. ..
- Robert I, Dantzer F, Reina San Martin B. Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination. J Exp Med. 2009;206:1047-56 pubmed publisher..Thus, we define Parp1 as facilitating alternative end-joining and Parp2 as a novel translocation suppressor during CSR. ..
- Catalan N, Selz F, Imai K, Revy P, Fischer A, Durandy A. 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. 2003;171:2504-9 pubmed
- Schrader C, Bradley S, Vardo J, Mochegova S, Flanagan E, Stavnezer J. Mutations occur in the Ig Smu region but rarely in Sgamma regions prior to class switch recombination. EMBO J. 2003;22:5893-903 pubmed..Finally, we find that mice expressing a transgene for terminal deoxynucleotidyl transferase (TdT) have nucleotide insertions at S-S junctions, indicating that the recombining DNA ends are accessible to end-processing enzyme activities. ..
- Begum N, Kinoshita K, Kakazu N, Muramatsu M, Nagaoka H, Shinkura R, et al. Uracil DNA glycosylase activity is dispensable for immunoglobulin class switch. Science. 2004;305:1160-3 pubmed..These results indicate that UNG is involved in the repair step of CSR yet by an unknown mechanism. The dispensability of U removal in the DNA cleavage step of CSR requires a reconsideration of the model of DNA deamination by AID. ..
- Xu Z, Fulop Z, Wu G, Pone E, Zhang J, Mai T, et al. 14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination. Nat Struct Mol Biol. 2010;17:1124-35 pubmed publisher..Finally, 14-3-3 proteins interacted directly with AID and enhanced AID-mediated in vitro DNA deamination, further emphasizing the important role of these adaptors in CSR. ..
- Nambu Y, Sugai M, Gonda H, Lee C, Katakai T, Agata Y, et al. Transcription-coupled events associating with immunoglobulin switch region chromatin. Science. 2003;302:2137-40 pubmed..These data indicate an important role of GLT in the regulation of chromatin accessibility, strongly suggesting that the target of AID is chromatin DNA. Our results give insights on the role of AID and the regulatory mechanism of CSR. ..
- Kuzin I, Ugine G, Wu D, Young F, Chen J, Bottaro A. Normal isotype switching in B cells lacking the I mu exon splice donor site: evidence for multiple I mu-like germline transcripts. J Immunol. 2000;164:1451-7 pubmed..We propose that all of these transcripts directly contribute to mu class switching activity. ..
- Lumsden J, McCarty T, Petiniot L, Shen R, Barlow C, Wynn T, et al. Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J Exp Med. 2004;200:1111-21 pubmed..These findings suggest a role of ATM in DNA DSB recognition and/or repair during CSR. ..
- Roy D, Yu K, Lieber M. Mechanism of R-loop formation at immunoglobulin class switch sequences. Mol Cell Biol. 2008;28:50-60 pubmed..This provides an independent basis for concluding that the primary function of G clustering, in the context of high G density, is R-loop formation. ..
- Rooney S, Alt F, Sekiguchi J, Manis J. Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proc Natl Acad Sci U S A. 2005;102:2471-5 pubmed..We found that ATM/Artemis double-deficient mice were viable and born in normal Mendelian numbers. Therefore, we conclude that DNA-PKcs has Artemis-independent functions in CSR and normal development. ..
- Xue K, Rada C, Neuberger M. The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2-/- ung-/- mice. J Exp Med. 2006;203:2085-94 pubmed
- Wang L, Whang N, Wuerffel R, Kenter A. AID-dependent histone acetylation is detected in immunoglobulin S regions. J Exp Med. 2006;203:215-26 pubmed..Our findings raise the intriguing possibility that histone H4 Ac at S regions is a marker for chromatin modifications associated with DSB repair during CSR. ..
- Wuerffel R, Wang L, Grigera F, Manis J, Selsing E, Perlot T, et al. S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity. 2007;27:711-22 pubmed..Thus, the S-S synaptosome is formed as a result of the self-organizing transcription system that regulates GLT expression and may serve to guard against spurious chromosomal translocations. ..
- Zarrin A, Alt F, Chaudhuri J, Stokes N, Kaushal D, Du Pasquier L, et al. An evolutionarily conserved target motif for immunoglobulin class-switch recombination. Nat Immunol. 2004;5:1275-81 pubmed..We propose that AGCT is a primordial CSR motif that targets AID through a non-R-loop mechanism involving an AID-replication protein A complex. ..
- Peron S, Pan Hammarstrom Q, Imai K, Du L, Taubenheim N, Sanal O, et al. A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair. J Exp Med. 2007;204:1207-16 pubmed..Overall, these findings suggest that a unique Ig CSR deficiency phenotype could be related to an as-yet-uncharacterized defect in a DNA repair pathway involved in both CSR and SHM events. ..
- Stavnezer J, Bradley S, Rousseau N, Pearson T, Shanmugam A, Waite D, et al. Switch recombination in a transfected plasmid occurs preferentially in a B cell line that undergoes switch recombination of its chromosomal Ig heavy chain genes. J Immunol. 1999;163:2028-40 pubmed..Fewer recombination events are detected in four different B and T cell lines that do not undergo switch recombination of their endogenous genes. ..
- Nagaoka H, Muramatsu M, Yamamura N, Kinoshita K, Honjo T. 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. 2002;195:529-34 pubmed..These findings strongly suggest that AID itself or a single molecule generated by RNA editing function of AID may mediate a common step of SHM and CSR, which is likely to be involved in DNA cleavage. ..
- Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, et al. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993;72:291-300 pubmed..The gene encoding gp39 was mapped to Xq26, the X chromosome region where the gene responsible for HIM had previously been mapped. These data suggest that a defect in gp39 is the basis of X-linked HIM. ..
- Arakawa H, Iwasato T, Hayashida H, Shimizu A, Honjo T, Yamagishi H. The complete murine immunoglobulin class switch region of the alpha heavy chain gene-hierarchic repetitive structure and recombination breakpoints. J Biol Chem. 1993;268:4651-5 pubmed..2-kb repetitive region. ..
- Huang F, Yu K, Balter B, Selsing E, Oruc Z, Khamlichi A, et al. Sequence dependence of chromosomal R-loops at the immunoglobulin heavy-chain Smu class switch region. Mol Cell Biol. 2007;27:5921-32 pubmed..These studies also provide the first analysis of how R-loop formation in the eukaryotic chromosome depends on the DNA sequence. ..
- Fossati Jimack L, Reininger L, Chicheportiche Y, Clynes R, Ravetch J, Honjo T, et al. High pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia. J Exp Med. 1999;190:1689-96 pubmed
- Rush J, Fugmann S, Schatz D. Staggered AID-dependent DNA double strand breaks are the predominant DNA lesions targeted to S mu in Ig class switch recombination. Int Immunol. 2004;16:549-57 pubmed
- Zeng X, Negrete G, Kasmer C, Yang W, Gearhart P. Absence of DNA polymerase eta reveals targeting of C mutations on the nontranscribed strand in immunoglobulin switch regions. J Exp Med. 2004;199:917-24 pubmed..This data shows for the first time that C is preferentially mutated in vivo and pol eta generates hypermutation in the mu and gamma switch regions. ..
- Iwasato T, Arakawa H, Shimizu A, Honjo T, Yamagishi H. Biased distribution of recombination sites within S regions upon immunoglobulin class switch recombination induced by transforming growth factor beta and lipopolysaccharide. J Exp Med. 1992;175:1539-46 pubmed..Our results support the hypotheses that TGF-beta increases the frequency of switch recombination events to IgA and that the switch recombination to IgA often proceeds by successive recombination of S mu/S gamma and S gamma/S alpha. ..
- Reina San Martin B, Difilippantonio S, Hanitsch L, Masilamani R, Nussenzweig A, Nussenzweig M. H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation. J Exp Med. 2003;197:1767-78 pubmed..Our results suggest a role for H2AX in regulating the higher order chromatin remodeling that facilitates switch region synapsis. ..
- Min I, Rothlein L, Schrader C, Stavnezer J, Selsing E. Shifts in targeting of class switch recombination sites in mice that lack mu switch region tandem repeats or Msh2. J Exp Med. 2005;201:1885-90 pubmed..We propose that Msh2 affects S site location because sequences with few activation-induced cytidine deaminase targets generate mostly switch DNA cleavages that require Msh2-directed processing to allow CSR joining. ..
- Boboila C, Jankovic M, Yan C, Wang J, Wesemann D, Zhang T, et al. Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci U S A. 2010;107:3034-9 pubmed publisher..IgH chromosomal translocations to the c-myc oncogene also are augmented in the combined absence of Ku70 and ligase 4. We discuss the implications of these findings for A-EJ in normal and abnormal DSB repair. ..
- Wang L, Wuerffel R, Feldman S, Khamlichi A, Kenter A. S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination. J Exp Med. 2009;206:1817-30 pubmed publisher..Thus, the histone methylation pattern produced by transcription localizes accessible chromatin to S regions, thereby focusing AID attack. ..
- Rajagopal D, Maul R, Ghosh A, Chakraborty T, Khamlichi A, Sen R, et al. Immunoglobulin switch mu sequence causes RNA polymerase II accumulation and reduces dA hypermutation. J Exp Med. 2009;206:1237-44 pubmed publisher..We propose that altered DNA structure in the switch region pauses RNA polymerase II and limits access of DNA polymerase eta during hypermutation. ..
- Wu X, Stavnezer J. DNA polymerase beta is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination. J Exp Med. 2007;204:1677-89 pubmed..We conclude that Polbeta attempts to faithfully repair S region lesions but fails to repair them all. ..
- Shinkura R, Tian M, Smith M, Chua K, Fujiwara Y, Alt F. The influence of transcriptional orientation on endogenous switch region function. Nat Immunol. 2003;4:435-41 pubmed..We propose that single-stranded DNA stabilized by transcription-dependent, higher order structures is a primary substrate of CSR. ..
- Dudley D, Manis J, Zarrin A, Kaylor L, Tian M, Alt F. Internal IgH class switch region deletions are position-independent and enhanced by AID expression. Proc Natl Acad Sci U S A. 2002;99:9984-9 pubmed
- Yu K, Roy D, Bayramyan M, Haworth I, Lieber M. Fine-structure analysis of activation-induced deaminase accessibility to class switch region R-loops. Mol Cell Biol. 2005;25:1730-6 pubmed..This phenomenon may explain the lack of WRC site preference at the mutations surrounding class switch recombination junctions. ..
- Tashiro J, Kinoshita K, Honjo T. Palindromic but not G-rich sequences are targets of class switch recombination. Int Immunol. 2001;13:495-505 pubmed..The results suggest that the secondary structure of S-region sequences which is transiently formed during transcription may be necessary for recognition by class switch recombinase. ..
- Shen H, Cheo D, Friedberg E, Storb U. The inactivation of the XP-C gene does not affect somatic hypermutation or class switch recombination of immunoglobulin genes. Mol Immunol. 1997;34:527-33 pubmed..Furthermore, we found that Ig gene switch recombination also is normal in these mice. ..
- Eccleston J, Schrader C, Yuan K, Stavnezer J, Selsing E. Class switch recombination efficiency and junction microhomology patterns in Msh2-, Mlh1-, and Exo1-deficient mice depend on the presence of mu switch region tandem repeats. J Immunol. 2009;183:1222-8 pubmed publisher..It is also possible that the inability to initiate MMR in the absence of Msh2 results in CSR junctions with less microhomology than joinings that occur when MMR is initiated but then proceeds abnormally due to Mlh1 or Exo1 deficiencies. ..
- Minegishi Y. [Molecular mechanisms of antibody generation]. Nihon Rinsho. 2005;63 Suppl 4:248-53 pubmed
- Nowak U, Matthews A, Zheng S, Chaudhuri J. The splicing regulator PTBP2 interacts with the cytidine deaminase AID and promotes binding of AID to switch-region DNA. Nat Immunol. 2011;12:160-6 pubmed publisher..PTBP2 is thus an effector of CSR that promotes the binding of AID to switch-region DNA. ..