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Tuning Somatic Hypermutation by Transcription

  • Conference paper
Mechanisms of B Cell Neoplasia 1998

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 246))

Abstract

The dependence of somatic hypermutation on transcription was studied in three mutant immunoglobulin heavy chain (IgH) insertion mice in which a targeted nonfunctional VHB1-8 passenger transgene was either placed under the transcriptional control of a truncated DQ52 promoter (pΔ), its own RNA polymerase II dependent IgH promoter (pII) or a RNA polymerase I dependent promoter (pI). The relative mutation-frequency of the VhBI-8 passenger transgene in memory B cells of pΔ, pi and pII mice (7%, 60% and 100%) correlated with the relative levels of transgene-specific pre-mRNA expressed in germinal center B cells isolated from the mutant mice (8%, 72% and 100%, respectively). These data indicate that the mutation load of rearranged Ig genes can be tuned by transcription. The question, whether somatic hypermutation requires transcription per se or a specific component of the RNA polymerase II complex, is under investigation.

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References

  • Alessandrini A, Desiderio SV (1991) Coordination of immunoglobulin DJH transcription and D-to-JH rearrangement by promoter-enhancer approximation. Mol Cell Biol 11: 2096 – 2107

    PubMed  CAS  Google Scholar 

  • Aoufouchi S, Yelamos J, Milstein C (1996) Nonsense mutations inhibit RNA splicing in a cell-free system: recognition of mutant codon is independent of protein synthesis. Cell 85: 415 – 422

    Article  PubMed  CAS  Google Scholar 

  • Betz AG, Milstein C, Gonzalez-Fernandez A, Pannell R, Larson T, Neuberger M S (1994) Elements regulating somatic hypermutation of an immunoglobulin kappa gene: critical role for the intron enhancer/matrix attachment region. Cell 77: 239 – 248

    Article  PubMed  CAS  Google Scholar 

  • Betz AG, Neuberger MS, Milstein C (1993) Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol Today 14: 405 – 411

    Article  PubMed  CAS  Google Scholar 

  • Cheng J, Maquat L E (1993) Nonsense codons can reduce the abundance of nuclear mRNA without affecting the abundance of pre-mRNA or the half-life of cytoplasmic mRNA. Mol Cell Biol 13: 1892 – 1902

    PubMed  CAS  Google Scholar 

  • Fukita Y, Jacobs H, Rajewsky K (1998) Somatic Hypermutation in the Heavy Chain Locus Correlates with Transcription. Immunity 9: 105 – 114

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Fernandez A, Gupta SK, Pannell R, Neuberger MS, Milstein C (1994) Somatic mutation of immunoglobulin lambda chains: a segment of the major intron hypermutates as much as the complementarity-determining regions. Proc Natl Acad Sci U S A 91: 12614 – 12618

    Article  PubMed  CAS  Google Scholar 

  • Goyenechea B, Klix N, Yelamos J, Williams GT, Riddell A, Neuberger MS, Milstein C (1997) Cells strongly expressing Ig(kappa) transgenes show clonal recruitment of hypermutation: a role for both MAR and the enhancers. Embo J 16: 3987 – 3994

    Article  PubMed  CAS  Google Scholar 

  • Grummt I, Skinner JA. (1985) Efficient transcription of a protein-coding gene from the RNA polymerase I promoter in transfected cells. Proc Natl Acad Sci U S A 82: 722 – 726

    Article  PubMed  CAS  Google Scholar 

  • Jacobs H, Fukita Y, van der Horst GTJ, de Boer J, Weeda G, Essers J, de Wind N, Engelward BP, Samson L, Verbeek S, Menissier de Murcia J, de Murcia G, te Riele H, Rajewsky K (1998) Hypermutation of Immunoglobulin Genes in Memory B cells of DNA repair-deficient Mice. J Exp Med 187: 1735 – 1743

    Article  PubMed  CAS  Google Scholar 

  • Kabat EA, Wu TT (1991) Identical V region amino acid sequences and segments of sequences in antibodies of different specificities. Relative contributions of VH and VL genes, minigenes, and complementarity-determining regions to binding of antibody-combining sites. J Immunol 147: 1709 – 1719

    PubMed  CAS  Google Scholar 

  • Klein U, Küppers R, Rajewsky, K (1997) Evidence for a large compartment of IgM-expressing memory B cells in humans. Blood 89: 1288 – 1298

    PubMed  CAS  Google Scholar 

  • Kottmann AH, Brack C, Eibel H, Kohler, G (1992) A survey of protein-DNA interaction sites within the murine immunoglobulin heavy chain locus reveals a particularly complex pattern around the DQ52 element. Eur J Immunol 22: 2113 – 2120

    Article  PubMed  CAS  Google Scholar 

  • Kottmann AH, Zevnik B, Welte M, Nielsen PJ, Kohler G (1994) A second promoter and enhancer element within the immunoglobulin heavy chain locus. Eur J Immunol 24: 817 – 821

    Article  PubMed  CAS  Google Scholar 

  • Kuhn A, Deppert U, Grummt I (1990) A 140-base-pair repetitive sequence element in the mouse rRNA gene spacer enhances transcription by RNA polymerase I in a cell-free system. Proc Natl Acad Sci U S A 87: 7527 – 7531

    Article  PubMed  CAS  Google Scholar 

  • Lozano F, Maertzdorf B, Pannell R, Milstein C (1994). Low cytoplasmic mRNA levels of immunoglobulin kappa light chain genes containing nonsense codons correlate with inefficient splicing. Embo J 13: 4617 – 4622

    PubMed  CAS  Google Scholar 

  • Maquat LE (1995) When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. Rna 1: 453 – 465

    PubMed  CAS  Google Scholar 

  • Orphanides G, Lagrange T, Reinberg D (1996) The general transcription factors of RNA polymerase II. Genes Dev 10: 2657 – 2683.

    Article  PubMed  CAS  Google Scholar 

  • Peltz SW, He F, Welch E, Jacobson A (1994) Nonsense-mediated mRNA decay in yeast. Prog Nucleic Acid Res Mol Biol 47: 271 – 298

    Article  PubMed  CAS  Google Scholar 

  • Peters A, Storb U (1996) Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 4: 57 – 65

    Article  PubMed  CAS  Google Scholar 

  • Rada C, Yelamos J, Dean W, Milstein C (1997) The 5’ hypermutation boundary of k chains is independent of local and neighbouring sequences and related to to the distance from the initiation of transcription. Eur J Immunol 27: 3115 – 3120

    Article  PubMed  CAS  Google Scholar 

  • Reeder RH (1990) rRNA synthesis in the nucleolus. Trends Genet 6:390–395

    Google Scholar 

  • 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: 1022 – 1026

    PubMed  CAS  Google Scholar 

  • Rogerson BJ (1994) Mapping the upstream boundary of somatic mutations in rearranged immunoglobulin transgenes and endogenous genes. Mol Immunol 31: 83 – 98

    Article  PubMed  CAS  Google Scholar 

  • Rogozin IB, Kolchanov NA (1992) Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. Biochim Biophys Acta 1171, 11 – 18

    PubMed  CAS  Google Scholar 

  • Rothenfluh HS, Taylor L, Bothwell AL, Both GW, Steele EJ (1993) Somatic hypermutation in 5’ flanking regions of heavy chain antibody variable regions. Eur J Immunol 23, 2152 – 2159

    Article  PubMed  CAS  Google Scholar 

  • Schreck R, Carey MF, Grummt I (1989) Transcriptional enhancement by upstream activators is brought about by different molecular mechanisms for class I and II RNA polymerase genes. Embo J 8: 3011 – 3017

    PubMed  CAS  Google Scholar 

  • Smale ST, Tjian R (1985) Transcription of herpes simplex virus tk sequences under the control of wild-type and mutant human RNA polymerase I promoters. Mol Cell Biol 5: 352 – 362

    PubMed  CAS  Google Scholar 

  • Taki S, Meiering M, Rajewsky K (1993) Targeted insertion of a variable region gene into the immunoglobulin heavy chain locus [see comments]. Science 262: 1268 – 1271

    Article  PubMed  CAS  Google Scholar 

  • Tumas-Brundage K, Manser, T (1997) The transcriptional promoter regulates hypermutation of the antibody heavy chain locus. J Exp Med 185: 239 – 250

    Article  PubMed  CAS  Google Scholar 

  • Wiesendanger M, Scharff MD, Edelman W (1998) Somatic Hypermutation, Transcription, and DNA Mismatch repair. Cell 94: 415 – 418

    Article  PubMed  CAS  Google Scholar 

  • Wood RD (1998) DNA repair: Knockouts still mutating after the first round. Curr Biology 8: 757 – 760

    Article  Google Scholar 

  • 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: 225 – 229

    Article  PubMed  CAS  Google Scholar 

  • Zawel L, Kumar, KP, and Reinberg, D (1995) Recycling of the general transcription factors during RNA polymerase II transcription. Genes Dev 9: 1479 - 1490

    Article  PubMed  CAS  Google Scholar 

  • Zawel L, Reinberg D (1992) Advances in RNA polymerase II transcription. Curr Opin Cell Biol 4: 488 – 495

    Article  PubMed  CAS  Google Scholar 

  • Zhang G, Taneja KL, Singer RH, Green MR (1994) Localization of pre-mRNA splicing in mammalian nuclei [see comments] Nature 372: 809 – 812

    CAS  Google Scholar 

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© 1999 Springer-Verlag Berlin Heidelberg

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Jacobs, H., Puglisi, A., Rajewsky, K., Fukita, Y. (1999). Tuning Somatic Hypermutation by Transcription. In: Melchers, F., Potter, M. (eds) Mechanisms of B Cell Neoplasia 1998. Current Topics in Microbiology and Immunology, vol 246. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60162-0_19

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  • DOI: https://doi.org/10.1007/978-3-642-60162-0_19

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64283-8

  • Online ISBN: 978-3-642-60162-0

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