Matthew D. Scharff, M.D.

Professor, Department of Cell Biology Chanin Bldg., Room 403 718 430-3527 scharff@aecom.yu.edu Biosketch Complete list of publications

Research interests Our laboratory is studying how antibody forming cells respond to antigen by undergoing somatic hypermutation and class and subclass switching so that they can produce higher affinity antibodies with more useful effector functions. The molecular and biochemical mechanisms of antibody V region hypermutation and class switch recombination is being studied in mice that are genetically defective in various repair proteins and in vitro in human Burkitt’s lymphoma cells which are undergoing V region mutation constitutively. These cell lines and genetically defective mice are being used to study the role of activation induced deaminase, mismatch repair and error prone polymerases in the hypermutation and isotype switching. These processes that can also lead to B cell lymphomas and we are trying to understand how mismatch repair protects B cells from undergoing malignant transformation while also contributing to the generation of antibody diversity. Chromatin immunoprecipitation and genetically manipulated and transfected Ig genes are being used to identify cis-acting DNA sequences and additional transacting proteins that target mutation and switching to Ig genes and mistarget them to proto-oncogenes. In a second project, we are using somatic mutation and isotype switching to generating better monoclonal antibodies that will protect from lethal toxins and emerging infections. Monoclonal antibodies to such toxins and viruses are generated and the impact of affinity and isotype are determined in vitro and in vivo.

Recent publications Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas..Alberto Martin, Philip D. Bardwell, Caroline J. Woo, Manxia Fan*, Marc J. Shulman, Matthew D. Scharff. Nature 415: 802, 2002.  The G-U mismatch glycosylase Mbd4 is dispensable for somatic mutation and class switch recombination. Philip D. Bardwell, Alberto Martin, Edmund Wong, Ziqiang Li, Winfried Edelmann and Matthew D. Scharff. J. Immunol. 170:1620-1624, 2003 Msh2 ATPase Activity is Essential for Somatic Hypermutation at A-T Basepairs and for Efficient Class Switch Recombination. Alberto Martin, Ziqiang Li, Diana Lin, Philip D. Bardwell, Maria D. Iglesias-Ussel Winfried Edelmann, and Matthew D. Scharff. J.Exp.Med. 198:1171-1178, 2003 Mutations in AID and UNG extend the function of AID. Ziqiang Li, Caroline Woo and Matthew D. Scharff. News and Views Nat Immunol. 4: 945-946, 2003 Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Ronda Bransteitter, Phuong Pham, Matthew D. Scharff and Myron F. Goodman. Proc. Natl. Acad. Sci. USA 100: 4102-4107, 2003.  Induction of somatic hypermutation is associated with modifications in immunoglobulin variable region chromatin. Caroline J. Woo, Alberto Martin, and Matthew D. Scharff Immunity 19:479-489, 2003.  Differential regulation of histone acetylation and generation of mutations in switch regions is associated with Ig class switching Li, Z, Luo, Z and Scharff, M.D. Proc Natl Acad Sci U S A.101:15428-33. 2004 Examination of Msh6- and Msh3-deficient Mice in Class Switching Reveals Overlapping and Distinct Roles of MutS Homologues in Antibody Diversification. Li Z, Scherer SJ, Ronai D, Iglesias-Ussel MD, Peled JU, Bardwell PD, Zhuang M, Lee K, Martin A, Edelmann W, Scharff MD. J Exp Med. 200, 47-59, 2004 The generation of antibody diversity through somatic hypermutation and class switch recombination. Li, Z.Woo, C. J. Iglesias-Ussel, M.D., Ronai, D., Scharff, M. D. Genes and Development, 18:1-11, 2004 The role of activation-induced cytidine deaminase in antibody diversification, immunodeficiency, and B-cell malignancies. Luo, Z, Ronai, D, and Scharff, M.D. J Allergy Clin Immunol. 114:726-35; 2004 Altered somatic hypermutation and reduced class switch recombination in Exonuclease 1-mutant mice. Philip D Bardwell, Caroline J Woo, Kaichun Wei, Ziqiang Li, Alberto Martin, Stephen Z Sack, Tchaiko Parris, Winfried Edelmann, and Matthew D Scharff Nat. Immunol. 5: 224-229, 2004.  Differential regulation of histone acetylation and generation of mutations in switch regions is associated with Ig class switching Li, Z, Luo, Z and Scharff, M.D. Proc Natl Acad Sci U S A.101:15428-33. 2004.  Identifying protein-protein interactions in somatic hypermutation. Goodman, M. F., Scharff, M. D. J Exp Med. 201:493-6, 2005 Cis-acting sequences in the IgH gene can regulate somatic mutation in hybridoma cells. D. Ronai, M.D. Iglesias-Ussel, M. Fan, M.J. Shulman, M.D. Scharff. PNAS. 102:11829-11834, 2005.  A role for Mlh3 in somatic hypermutation. Ziqiang Li , Jonathan Peled, Chunfang Zhao, Anton Svetlanov, Diana Ronai, Paula E. Cohen, and Matthew D. Scharff. DNA Repair. 5:675-682, 2006  The mismatch repair protein Msh6 plays a role in the targeting of AID to the Ig locus in vivo. Z. Li, C. Zhao, Z. Polonskaya, M. Zhuang, G. Yang, M.D. Iglesias-Ussel, Z. Luo, W. Edelmann, M.D. Scharff. Immunity 393-403, 2006.  A role for Mlh3 in somatic hypermutation. Ziqiang Li , Jonathan Peled, Chunfang Zhao, Anton Svetlanov, Diana Ronai, Paula E. Cohen, and Matthew D. Scharff. DNA Repair. 5:675-682, 2006.  Tumor necrosis factor-α and CD40L modulate cell surface morphology and induce aggregation in Ramos Burkitt's lymphoma cells. Laskov, R., N. Berger, M.D. Scharff, and M.S.Horwitz. Leukemia & Lymphoma. 47:507-519, 2006 Mouse models revealed the mechanisms for somatic hypermutation and class switch recombination of immunoglobulin genes. Maria D. Iglesias-Ussel, Ziqiang Li, and Matthew D. Scharff. Chapter of the book “The Mouse in Biomedical Research”, 2nd edition. Elsevier.  J. G. Fox et al eds. Vol 4, pages 155-168. 2007. Detection of Chromatin-Associated ssDNA in Regions Targeted for Somatic Hypermutation. Ronai, D., Iglesias-Ussel. M.D., Fan, M., Li, Z., Martin, A and M. D. Scharff. J. Exp. Med. 204:181-190, 2007 Targeting AID to the Ig genes. Mechanisms of Lymphocyte Activation and Immune Regulation. Li Z, Luo Z, Ronai D, Kuang FL, Peled JU, Iglesias-Ussel MD, Scharff M.D. Adv Exp. Med. Biol. 596:93-109, 2007 AID initiated purposeful mutations in immunoglobulin genes. Myron F. Goodman, Matthew D. Scharff and Floyd E. Romesberg. Advances in Immunology. 94:127-155, 2007

Matthew Scharff: Research interests | Biosketch Faculty research at a glance Birshtein | Bouhassira | Edelmann | Fyodorov | Keogh | Kielian | Kitsis | Nathenson | Query Scharff | Schildkraut | Shafritz | Singer | Skoultchi | Stanley | Steidl |Warner | Ye   Home