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    Janet Stavnezer PhD

    TitleProfessor Emeritus
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-4100
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentPathology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

        Overview 
        Narrative

        Academic Background

        PhD, Johns Hopkins University, 1971

        Janet Stavnezer, PhD

        Mechanism and Regulation of Antibody Class Switch Recombination

        B cells respond to immunization or infection by diversifying the antibodies they produce through two processes: antibody class switch recombination and somatic hypermutation of their antigen-binding regions. Switch recombination causes a change in antibody class expression from IgM to IgG, IgA or IgE, resulting in an increased ability of the antibody to remove the pathogen. Somatic hypermutation, in conjunction with B cell selection, results in increases in the antigen binding ability of the antibody.

        Both class switch recombination and somatic hypermutation are initiated by the enzyme activation induced cytidine deaminase (AID), acting on the antibody genes. After AID acts, two different DNA repair pathways (base excision repair and mismatch repair) begin to attempt to repair the resulting dU bases. However, instead of accurately repairing the lesions, these repair processes result in the introduction of DNA breaks and mutations that lead to class switch recombination and mutation of the variable region genes. The figure below diagrams the process of class switch recombination.

        The AID enzyme is highly induced in activated B cells, including germinal center B cells, and only occasionally found in other cell types, and sometimes in tumor cells. Although essential for a proper immune response, it is also dangerous as it occasionally targets non-Ig genes. We have performed a genomics search to attempt to identify genes targeted by AID, as evidenced by the presence of DNA double-strand breaks. We have identified reproducible AID-dependent DNA breaks that occur at several genomic sites. We are investigating whether these sites might be important for generation of B cell lymphomas, as it is known that translocations between S regions and oncogenes occur in activated B cells, and that this can lead to B cell lymphoma. We are currently investigating several aspects of these findings, for example, how AID is normally properly targeted to S regions, and how the DNA breaks introduced in S regions are normally properly shepherded toward class switch recombination.

        Another project is to investigate why the C terminal 10 amino acids of AID are required for CSR but not for SHM. Our initial results have been published (Ranjit et al, 2011), and we are continuing to investigate the hypothesis that the C terminus recruits proteins involved in recombination of DNA breaks.

        Diagram of Class Switch Recombination (CSR)

        Diagram of Class Switch Recombination (CSR)

        Top line shows Ig heavy chain genes in a B cell that expresses IgM and IgD (by alternative RNA processing). CSR occurs after AID deaminates dC residues within S regions that are transcriptionally active. RNA transcripts from the unrearranged heavy chain genes are called germline transcripts.

        Middle line illustrates the intrachromosomal deletional recombination between two switch (S) regions during CSR from IgM to IgE. The DNA in between Sm and Se is excised from the chromosome as a circle.

        Bottom line illustrates the chromosome after CSR showing that the identical VH region originally expressed with the Cmgene is now expressed with Ce gene in cells expressing IgE.



        Bibliographic 
        selected publications
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        1. Kadungure T, Ucher AJ, Linehan EK, Schrader CE, Stavnezer J. Individual Substitution Mutations in the AID C Terminus That Ablate IgH Class Switch Recombination. PLoS One. 2015; 10(8):e0134397.
          View in: PubMed
        2. Khair L, Baker RE, Linehan EK, Schrader CE, Stavnezer J. Nbs1 ChIP-Seq Identifies Off-Target DNA Double-Strand Breaks Induced by AID in Activated Splenic B Cells. PLoS Genet. 2015 Aug; 11(8):e1005438.
          View in: PubMed
        3. Stavnezer J, Schrader CE. Response to Comment on "IgH Chain Class Switch Recombination: Mechanism and Regulation". J Immunol. 2015 Mar 1; 194(5):2040.
          View in: PubMed
        4. Stavnezer J, Schrader CE. IgH chain class switch recombination: mechanism and regulation. J Immunol. 2014 Dec 1; 193(11):5370-8.
          View in: PubMed
        5. Ucher AJ, Ranjit S, Kadungure T, Linehan EK, Khair L, Xie E, Limauro J, Rauch KS, Schrader CE, Stavnezer J. Mismatch repair proteins and AID activity are required for the dominant negative function of C-terminally deleted AID in class switching. J Immunol. 2014 Aug 1; 193(3):1440-50.
          View in: PubMed
        6. Peng M, Xie J, Ucher A, Stavnezer J, Cantor SB. Crosstalk between BRCA-Fanconi anemia and mismatch repair pathways prevents MSH2-dependent aberrant DNA damage responses. EMBO J. 2014 Aug 1; 33(15):1698-712.
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        7. Stavnezer J, Linehan EK, Thompson MR, Habboub G, Ucher AJ, Kadungure T, Tsuchimoto D, Nakabeppu Y, Schrader CE. Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation. Proc Natl Acad Sci U S A. 2014 Jun 24; 111(25):9217-22.
          View in: PubMed
        8. Khair L, Guikema JE, Linehan EK, Ucher AJ, Leus NG, Ogilvie C, Lou Z, Schrader CE, Stavnezer J. ATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination. J Immunol. 2014 May 15; 192(10):4887-96.
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        9. 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. A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination. Nat Immunol. 2013 Nov; 14(11):1183-9.
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        10. Schrader CE, Linehan EK, Ucher AJ, Bertocci B, Stavnezer J. DNA polymerases ß and ? do not directly affect Ig variable region somatic hypermutation although their absence reduces the frequency of mutations. DNA Repair (Amst). 2013 Dec; 12(12):1087-93.
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        11. Hasham MG, Snow KJ, Donghia NM, Branca JA, Lessard MD, Stavnezer J, Shopland LS, Mills KD. Activation-induced cytidine deaminase-initiated off-target DNA breaks are detected and resolved during S phase. J Immunol. 2012 Sep 1; 189(5):2374-82.
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        12. Ucher AJ, Linehan EK, Teebor GW, Schrader CE, Stavnezer J. The DNA glycosylases Ogg1 and Nth1 do not contribute to Ig class switching in activated mouse splenic B cells. PLoS One. 2012; 7(4):e36061.
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        13. Ranjit S, Khair L, Linehan EK, Ucher AJ, Chakrabarti M, Schrader CE, Stavnezer J. AID recruits UNG and Msh2 to Ig switch regions dependent upon the AID C terminus [corrected]. J Immunol. 2011 Sep 1; 187(5):2464-75.
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        14. Stavnezer J. Complex regulation and function of activation-induced cytidine deaminase. Trends Immunol. 2011 May; 32(5):194-201.
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        15. Staszewski O, Baker RE, Ucher AJ, Martier R, Stavnezer J, Guikema JE. Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells. Mol Cell. 2011 Jan 21; 41(2):232-42.
          View in: PubMed
        16. Guikema JE, Schrader CE, Brodsky MH, Linehan EK, Richards A, El Falaky N, Li DH, Sluss HK, Szomolanyi-Tsuda E, Stavnezer J. p53 represses class switch recombination to IgG2a through its antioxidant function. J Immunol. 2010 Jun 1; 184(11):6177-87.
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        17. Stavnezer J, Björkman A, Du L, Cagigi A, Pan-Hammarström Q. Mapping of switch recombination junctions, a tool for studying DNA repair pathways during immunoglobulin class switching. Adv Immunol. 2010; 108:45-109.
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        18. Eccleston J, Schrader CE, 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 Jul 15; 183(2):1222-8.
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        19. Schrader CE, Guikema JE, Wu X, Stavnezer J. The roles of APE1, APE2, DNA polymerase beta and mismatch repair in creating S region DNA breaks during antibody class switch. Philos Trans R Soc Lond B Biol Sci. 2009 Mar 12; 364(1517):645-52.
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        20. Stavnezer J, Kang J. The surprising discovery that TGF beta specifically induces the IgA class switch. J Immunol. 2009 Jan 1; 182(1):5-7.
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        21. Guikema JE, Schrader CE, Leus NG, Ucher A, Linehan EK, Werling U, Edelmann W, Stavnezer J. Reassessment of the role of Mut S homolog 5 in Ig class switch recombination shows lack of involvement in cis- and trans-switching. J Immunol. 2008 Dec 15; 181(12):8450-9.
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        22. Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol. 2008; 26:261-92.
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        23. Guikema JE, Linehan EK, Tsuchimoto D, Nakabeppu Y, Strauss PR, Stavnezer J, Schrader CE. APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination. J Exp Med. 2007 Nov 26; 204(12):3017-26.
          View in: PubMed
        24. Schrader CE, Guikema JE, Linehan EK, Selsing E, Stavnezer J. Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair. J Immunol. 2007 Nov 1; 179(9):6064-71.
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        25. 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 Jul 9; 204(7):1677-89.
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        26. Kaminski DA, Stavnezer J. Stimuli that enhance IgA class switching increase histone 3 acetylation at S alpha, but poorly stimulate sequential switching from IgG2b. Eur J Immunol. 2007 Jan; 37(1):240-51.
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        27. Kaminski DA, Stavnezer J. Enhanced IgA class switching in marginal zone and B1 B cells relative to follicular/B2 B cells. J Immunol. 2006 Nov 1; 177(9):6025-9.
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        28. Bradley SP, Kaminski DA, Peters AH, Jenuwein T, Stavnezer J. The histone methyltransferase Suv39h1 increases class switch recombination specifically to IgA. J Immunol. 2006 Jul 15; 177(2):1179-88.
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        29. Stavnezer J, Schrader CE. Mismatch repair converts AID-instigated nicks to double-strand breaks for antibody class-switch recombination. Trends Genet. 2006 Jan; 22(1):23-8.
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        30. Schrader CE, Linehan EK, Mochegova SN, Woodland RT, Stavnezer J. Inducible DNA breaks in Ig S regions are dependent on AID and UNG. J Exp Med. 2005 Aug 15; 202(4):561-8.
          View in: PubMed
        31. Min IM, Rothlein LR, Schrader CE, 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 Jun 20; 201(12):1885-90.
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        32. Stavnezer J, Amemiya CT. Evolution of isotype switching. Semin Immunol. 2004 Aug; 16(4):257-75.
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        33. Kaminski DA, Stavnezer J. Antibody class switching: uncoupling S region accessibility from transcription. Trends Genet. 2004 Aug; 20(8):337-40.
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        34. Schrader CE, Vardo J, Linehan E, Twarog MZ, Niedernhofer LJ, Hoeijmakers JH, Stavnezer J. Deletion of the nucleotide excision repair gene Ercc1 reduces immunoglobulin class switching and alters mutations near switch recombination junctions. J Exp Med. 2004 Aug 2; 200(3):321-30.
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        35. Schrader CE, Bradley SP, Vardo J, Mochegova SN, Flanagan E, Stavnezer J. Mutations occur in the Ig Smu region but rarely in Sgamma regions prior to class switch recombination. EMBO J. 2003 Nov 3; 22(21):5893-903.
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        36. Min IM, Schrader CE, Vardo J, Luby TM, D'Avirro N, Stavnezer J, Selsing E. The Smu tandem repeat region is critical for Ig isotype switching in the absence of Msh2. Immunity. 2003 Oct; 19(4):515-24.
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        37. Schrader CE, Vardo J, Stavnezer J. Mlh1 can function in antibody class switch recombination independently of Msh2. J Exp Med. 2003 May 19; 197(10):1377-83.
          View in: PubMed
        38. Storb U, Stavnezer J. Immunoglobulin genes: generating diversity with AID and UNG. Curr Biol. 2002 Oct 29; 12(21):R725-7.
          View in: PubMed
        39. Schrader CE, Vardo J, Stavnezer J. Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions. J Exp Med. 2002 Feb 4; 195(3):367-73.
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        40. Luby TM, Schrader CE, Stavnezer J, Selsing E. The mu switch region tandem repeats are important, but not required, for antibody class switch recombination. J Exp Med. 2001 Jan 15; 193(2):159-68.
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        41. Schrader CE, Edelmann W, Kucherlapati R, Stavnezer J. Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes. J Exp Med. 1999 Aug 2; 190(3):323-30.
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        42. Qiu G, Harriman GR, Stavnezer J. 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. 1999 Jan; 11(1):37-46.
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        43. Lin SC, Wortis HH, Stavnezer J. The ability of CD40L, but not lipopolysaccharide, to initiate immunoglobulin switching to immunoglobulin G1 is explained by differential induction of NF-kappaB/Rel proteins. Mol Cell Biol. 1998 Sep; 18(9):5523-32.
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        44. Shen CH, Stavnezer J. Interaction of stat6 and NF-kappaB: direct association and synergistic activation of interleukin-4-induced transcription. Mol Cell Biol. 1998 Jun; 18(6):3395-404.
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        45. Lin SC, Stavnezer J. Activation of NF-kappaB/Rel by CD40 engagement induces the mouse germ line immunoglobulin Cgamma1 promoter. Mol Cell Biol. 1996 Sep; 16(9):4591-603.
          View in: PubMed
        46. Stavnezer J. Antibody class switching. Adv Immunol. 1996; 61:79-146.
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        47. Stavnezer J. Regulation of antibody production and class switching by TGF-beta. J Immunol. 1995 Aug 15; 155(4):1647-51.
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        48. Delphin S, Stavnezer J. Characterization of an interleukin 4 (IL-4) responsive region in the immunoglobulin heavy chain germline epsilon promoter: regulation by NF-IL-4, a C/EBP family member and NF-kappa B/p50. J Exp Med. 1995 Jan 1; 181(1):181-92.
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        49. Shockett P, Stavnezer J. Inhibitors of poly(ADP-ribose) polymerase increase antibody class switching. J Immunol. 1993 Dec 15; 151(12):6962-76.
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        50. Xu MZ, Stavnezer J. Regulation of transcription of immunoglobulin germ-line gamma 1 RNA: analysis of the promoter/enhancer. EMBO J. 1992 Jan; 11(1):145-55.
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        51. Severinson E, Fernandez C, Stavnezer J. Induction of germ-line immunoglobulin heavy chain transcripts by mitogens and interleukins prior to switch recombination. Eur J Immunol. 1990 May; 20(5):1079-84.
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        52. Dunnick W, Stavnezer J. Copy choice mechanism of immunoglobulin heavy-chain switch recombination. Mol Cell Biol. 1990 Jan; 10(1):397-400.
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        53. Waters SH, Saikh KU, Stavnezer J. A B-cell-specific nuclear protein that binds to DNA sites 5' to immunoglobulin S alpha tandem repeats is regulated during differentiation. Mol Cell Biol. 1989 Dec; 9(12):5594-601.
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        54. Dunnick W, Wilson M, Stavnezer J. Mutations, duplication, and deletion of recombined switch regions suggest a role for DNA replication in the immunoglobulin heavy-chain switch. Mol Cell Biol. 1989 May; 9(5):1850-6.
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        55. Stavnezer J, Radcliffe G, Lin YC, Nietupski J, Berggren L, Sitia R, Severinson E. Immunoglobulin heavy-chain switching may be directed by prior induction of transcripts from constant-region genes. Proc Natl Acad Sci U S A. 1988 Oct; 85(20):7704-8.
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        56. Stavnezer J, Sirlin S, Abbott J. Induction of immunoglobulin isotype switching in cultured I.29 B lymphoma cells. Characterization of the accompanying rearrangements of heavy chain genes. J Exp Med. 1985 Mar 1; 161(3):577-601.
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