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ALBERTO MARTIN, Ph.D.

Diversification of the antibody response: Mutational mechanisms and contributions to oncogenesis.

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Department of Immunology
Medical Sciences Building 7302
1 King's College Circle
Toronto, Ontario M5S 1A8
Tel: (416) 978-4230
Fax: (416) 978-1938
E-mail: alberto.martin@utoronto.ca

Canada Research Chair in Antibody Diversification

 



Go to Alberto Martin's homepage

Diversification of the antibody response: Mutational mechanisms and contributions to oncogenesis.

Generation of antibody diversity in mature B cells. The antigen binding site of antibodies are created in immature B cells by the random assembly of variable (V), diversity (D), and joining (J) segments into one coding exon by a process termed V(D)J recombination. This process creates a very large repertoire of antibodies with different specificities. However, most antibodies that are generated bind to antigens such as viruses and bacteria with low affinity. In order to neutralize and clear pathogens and toxins from the circulation, B-cells must produce and secrete antibodies of higher affinity and of different classes. Following exposure to antigen, the V regions of the antibody genes acquire many base changes that result in antibodies that bind with higher affinities to their respective antigens. This phenomenon is achieved by the somatic hypermutation process. The constant region of the antibody gene encodes the remaining part of the antibody molecule and is responsible for carrying out the effector functions of the antibody. Constant regions, which define the antibody class, can be replaced with other constant regions by the class switch recombination process, thereby changing the antibody effector functions without changing the antigen binding site.

Our current research interests can be divided into three main areas, each of which is supported by external research funding.

AID in antibody diversification. The discovery of the B cell-specific activation-induced cytidine deaminase (AID) gene has resulted in a dramatic leap forward in our understanding of the processes of somatic hypermutation and class switch recombination. Mice and humans deficient in AID are incapable of somatic hypermutation and class switch recombination, while overexpression of AID can induce somatic hypermutation and class switch recombination in most cell types. Thus, AID is the only B cell specific protein that is required for both of these processes. AID initiates the processes of antibody diversification by deaminating cytidines within the V regions for somatic hypermutation and switch regions for class switch recombination. Current work in the laboratory is centered on delineating the molecular mechanisms of the somatic hypermutation and class switch recombination processes including the DNA repair proteins that repair the AID-induced DNA lesions.

The molecular basis for germinal center selection. In spite of intensive study of the germinal center, we still do not understand how B cells that acquire deleterious mutations in their antibody genes are dealt with, whether there is truly a survival advantage for B cells that harbour high-affinity antibodies, and what molecules would influence life versus death decisions within the germinal center, the site where high-affinity B cells are produced. Using unique systems combined with various gene-targeted mice, we are addressing these fundamental questions which will provide new insights into the affinity maturation process.

The molecular mechanisms of cancer development. We have two main cancer projects in the laboratory. In one project, we are investigating the etiology of lymphomas which encompass a variety of cancers specific to the lymphatic system, most of which are of B-cell origin. The etiology of these cancers is not known, but are likely driven by genomic instabilities in B lymphocytes that result in chromosomal translocations or other mutagenic DNA lesions. The most common lymphomas (i.e. diffuse large cell lymphoma, chronic lymphocytic leukemia, and Burkitt’s lymphoma) resemble either centroblasts or post-centroblasts. This and the fact many of these lymphomas have chromosomal translocations involving antibody genes suggests that antibody diversification processes are central to the development of these types of lymphomas. Our current work is investigating the role of AID and the oncogene c-myc in the transformation process, and the role of the mismatch repair pathway in suppressing the oncogenic transformation of lymphocytes.

The second cancer project in the laboratory is focused on uncovering the etiology of colorectal cancer, which is the third most common type of cancer and leading cause of cancer related deaths. Specific genetic mutations are linked to colorectal cancer development, and mutations in genes involved in mismatch repair are one of the most common types of genetic deficiencies that predispose to this type of cancer. The normal function of mismatch repair is to repair mutations produced during DNA replication. In the absence of mismatch repair, mutations accumulate throughout the genome. However, it is not clear why mismatch repair deficiency leads specifically to an increased risk in developing colon cancer, and our laboratories research focus is aimed at uncovering this mystery.

Select Publications.

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B. Boulianne, O. Rojas, D. Haddad, A. Zaheen, A. Kapelnikov, T. Nguyen, J. Gommerman*, Alberto Martin*  (2013) AID and Caspase 8 shape the germinal center response through apoptosis. J. Immunology.  In Press

 B. Boulianne, M. Le, L. Ward, L. Meng, Alberto Martin*, J. Gommerman* (2013) Lymph Node Germinal Centers form in the absence of Follicular Dendritic Cells, but their maintenance and function requires Lymphotoxin-b Receptor signaling. J. Immunology.  In Press

 A. Belcheva, B. Green, A. Weiss, C. Streutker, Alberto Martin* (2013). Elevated incidence of polyp formation in APCMin/+Msh2-/- mice is independent of nitric oxide-induced DNA mutations. PLOS One. Vol. 8(5), e65204.

 G. Galicia-Rosas, B. Boulianne, N. Pikor, Alberto Martin, J. Gommerman (2013) Secondary B cell Receptor diversification is necessary for T cell mediated neuroinflammation during Experimental Autoimmune Encephalomyelitis. PLOS One. Vol. 8(4), e61478.

 H. Li, R.M. Nepal, Alberto Martin, S. Berger (2012). Induction of apoptosis in Eμ-myc lymphoma cells in vitro and in vivo through calpain inhibition. Expt. Hematology. Vol. 40, p. 548-563.

 J. Parsa, S. Ramachandran, A. Zaheen, R. Nepal, A. Kapelnikov, A. Belcheva, M. Berru, D. Ronai, Alberto Martin* (2012). Negative supercoiling creates single-stranded patches of DNA that are substrates for AID-mediated mutagenesis. PLoS Genetics. Vol. 8, e1002518.

 A. Dancyger, J. King, M. Quinlan, H. Fifield, S. Tucker, H. Saunders, M. Berru, B. Magor, Alberto Martin, M. Larijani (2012). Differences in the enzymatic efficiency of bony fish and human AID are mediated by a single residue in the C-terminus that modulates single-stranded DNA binding. FASEB J. Vol. 26, p.1517-25.

 J.H. Fritz, O. Lucia Rojas, N. Simard, D. McCarthy, S. Hapfelmeier, S. Rubino, S. Robertson, M. Larijani, J. Gosselin, I. Ivanov, Alberto Martin, R. Casellas, D. Philpott, S. Girardin, K. McCoy, A. Macpherson, C. Paige and J. Gommerman (2011). Acquisition of a multifunctional TNF/iNOS-producing IgA+ plasma cell phenotype in the gut. Nature. Vol. 481, p.199-203.

 B. Green, A, Belcheva, R.M. Nepal, B. Boulianne, A. Martin (2011) The mismatch repair pathway functions normally at a non-AID target in germinal center B cells. Blood. Vol. 118, p. 3013-8.

 S. Ramachandran, R. Chahwan, R.M. Nepal, D. Frieder, S. Panier, A. Zaheen, D. Durocher, M. Scharff, and A. Martin (2010). The RNF8/RNF168 ubiquitin ligase cascade is required for class switch recombination. Proc Natl Acad Sci USA. Vol. 107, p. 809-814

 R.M. Nepal, L. Tong, B. Kolaj, W. Edelmann, A. Martin (2009). Msh2-dependent DNA repair mitigates a unique susceptibility of B cell progenitors to c-myc-induced lymphomas. Proc Natl Acad Sci USA. Vol. 106, p. 18698-703.

 D. Frieder, M. Larijani, C. Collins, M. Shulman, A. Martin (2009). The concerted action of Msh2 & UNG stimulates error-prone repair at A:T basepairs in hypermutating B cells. Mol Cell Biol. Vol. 18, p. 5148-57.

 A. Zaheen, B. Boulianne, S. Ramachandran, J. Parsa, J. Gommerman, A. Martin (2009). AID constrains Germinal Center size by Rendering B cells Susceptible to Apoptosis. Blood. Vol. 114, p.547-554.

 R.M. Nepal, A. Zaheen, W. Basit, L. Li, S.A. Berger, A. Martin (2008). AID and RAG1 do not contribute to lymphomagenesis in Em c-myc transgenic mice. Oncogene. Vol. 27, p.4752-6

 M. Larijani, A. Martin (2007). ssDNA structure and positional context of the target cytidine determine the enzymatic efficiency of AID. Mol Cell Biol. Vol. 27, p. 8038-48.

 D. Ronai, M.D. Iglesias-Ussel, M. Fan, Z. Li, A. Martin, M.D. Scharff (2007) Detection of Chromatin-Associated ssDNA in Regions Targeted for Somatic Hypermutation. J. Exp. Med. Vol. 204, p.181-190.

 Larijani, A. Petrov, O. Kolenchenko, M. Berru, S. Krylov and A. Martin (2007). AID associates with single-stranded DNA with high affinity and a long complex half-life in a sequence-independent manner. Mol Cell Biol. Vol. 27, p. 20-30.

 P. Bardwell, C. Woo, K. Wei, Z. Li, A. Martin , S. Sack, W. Edelmann, M Scharff (2003). Altered somatic hypermutation and reduced class switch recombination in Exonuclease 1-mutant mice. Nat. Immunol. Vol. 5, p. 224-229.

 A. Martin , Z. Li, D Lin, P. Bardwell, M. Iglesias, W. Edelmann, M. Scharff (2003). ATPase activity of Msh2 is essential for somatic hypermutation at A-T basepairs and for efficient class switch recombination. J. Exp. Med. Vol. 200, p.47-59.

 C. Woo, A. Martin , M. Scharff (2003). Induction of somatic hypermutation is associated with modifications in immunoglobulin variable region chromatin. Immunity. Vol. 19, p. 479-489.

 A. Martin and M. Scharff (2002) Somatic hypermutation of the AID transgene in B and non-B cells. Proc Natl Acad Sci USA. Vol. 99, p. 12304.

 A. Martin and M. Scharff (2002) AID and mismatch repair in antibody diversification. Nat. Rev. Immunol., Vol. 2, p. 605.

 A. Martin , P. Bardwell, C. Woo, M. Fan, M. Shulman, M. Scharff (2002) Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature, Vol. 415, p. 802-806.