Alberto Martin
PhD
Dr. Martin also maintains a lab website
Research
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.
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.
Gut microbiota and disease
Although the gut microbiota has beneficial effects to the host, it has also been linked to the development of certain pathological disorders, including inflammatory bowel diseases, and possibly colorectal cancer. Using an animal model of colorectal cancer (i.e. mismatch repair deficiency), we showed that the gut microbiota promotes this disease. While this work seems quite distinct to the work outlined above, the common theme is the mismatch repair system since this DNA repair pathway plays an essential role in somatic hypermutation and class switch recombination as well as in colon cancer. We currently have two questions that are designed to characterize the mouse model of colorectal cancer: (1) which bacterial species and what metabolite is/are promoting the development of colorectal cancer? (2) What is the underlying mechanism by which this occurs?
We are also carrying out research on gut microbiota and the etiology of inflammatory bowel disease (IBD). Our work centers on characterizing specific microbes and their role in IBD. As IBD patients are prone to develop colon cancer, our research on these microbes also encompass uncovering the mechanism of colitis associated colon cancer.
Recent Publications
2018
S. Nordermeer, S. Adam, D. Setiaputra, M. Barazas, S. Pettitt, A. Ling, M. Olivieri, A. Alvarez Quilon, N. Moatti, M. Zimmermann, S. Annunziato, D. Krastev, A. Sherker, S. Landry, R. Szilard, M. Munro, A. McEwan, T. Goullet de Rugy, Z. Lin, T. Hart, J. Moffat, A. Gingras, Alberto Martin, H. van Attikum, J. Jonkers, C. Lord, S. Rottenberg, D. Durocher (2018) The Shieldin complex mediates 53BP1-dependent DNA repair. Nature. In press
M. Tanaka, J. Fine, C. Kirkham, O. Aguilar, A. Belcheva, Alberto Martin, T. Ketela, J. Moffat, D. Allan, J. Carlyle (2018) The inhibitory NKR-P1B:Clr-b recognition axis facilitates detection of oncogenic transformation and cancer immunosurveillance. Cancer Research. In press
C. Li, T. Irrazabal, C. So, M. Berru, L. Du, E. Lam, J. Gommerman, Q. Pan-Hammarström, & Alberto Martin* (2018) The H2B deubiquitinase Usp22 promotes antibody class switch recombination by facilitating non homologous end joining. Nature Communications. Vol 9, p1-12
A. Ling, C. So, M. Le, A. Chen, L. Hung, Alberto Martin* (2018) Double stranded DNA break polarity skews repair pathway choice during intra- and inter-chromosomal recombination. PNAS USA. Vol 115, p2800-2805
B. Green, Alberto Martin, A. Belcheva (2018) Deficiency in the DNA glycosylases UNG1 and OGG1 does not potentiate c-Myc-induced B cell lymphomagenesis. Experimental Hematology, In press.
C. Maisonneuve, T. Irrazabal, Alberto Martin, S. Girardin, & D. Philpott (2018) The impact of the gut microbiome on colorectal cancer. Annual Review Cancer Biology. Vol 2, p. 229-249.
T. Irrazabal, Alberto Martin* (2018) Microbiota and Colon Cancer: Orchestrating neoplasia through DNA damage and immune dysregliation. Encyclopedia of Cancer, 3rd edition. Elsevier, In press
2017
S. Oke, Alberto Martin* (2017) Insights into the role of the intestinal microbiota in colon cancer. Therapeutic Advances in Gastroenterology. In Press
K. Bromberg, T. Mitchell, A. Upadhyay, C. Jakob, L. Lasko, C. Li, C. Tuzon, Y. Dai, F. Li, M. Eram, A. Nuber, N. Soni, V. Manaves, M. Algire, R. Sweis, M. Torrent, G. Schotta, C. Sun, M. Michaelides, A. Shoemaker, C. Arrowsmith, P. Brown, V. Santhakumar, Alberto Martin, J. Rice, G. Chiang, M. Vedadi, D. Barsyte-Lovejoy and W. Pappano (2017) The novel SUV4-20 inhibitor A-196 verifies a role for epigenetics in the maintenance of genomic integrity. Nat Chem Biol. Vol 13, p317-324
2016
M. Le , D. Haddad , A. Ling, C. Li, C. So, A. Chopra, R. Hu, J. Angulo, J. Moffat, Alberto Martin* (2016) Kin17 facilitates multiple double-strand break repair pathways that govern B cell class switching. Scientific Reports 6:37215
S. Ramachandran, D. Haddad, C. Li, M. Le, A. Ling, C. So, R. Nepal, J. Gommerman, K. Yu, T. Ketela, J. Moffat, Alberto Martin* (2016) The SAGA deubiquitination module promotes DNA repair and class switch recombination through DNAPK-mediated gH2AX formation. Cell Reports. Vol. 15, p1554–1565
S. Li & Alberto Martin* (2016) Mismatch Repair and Colon Cancer: Mechanisms and Therapies Explored. Trends in Molecular Medicine. Vol 22, p. 274-289
S. Ramachandran & Alberto Martin* (2016) DNA repair during class switch recombination. Encyclopedia of Immunobiology. Elsevier.
2015
Irrazábal* & Alberto Martin* (2015) T regulatory cells gone bad: An oncogenic immune response against enterotoxigenic B. fragilis infection leads to colon cancer. Cancer Discovery. Vol. 5, p. 1021-1023
A. Belcheva*, T. Irrazábal, Alberto Martin* (2015) Gut microbial metabolism and colon cancer: Can manipulations of the microbiota be useful in the management of gastrointestinal health. BioEssays. Vol. 37, p. 403-12
A. Belcheva & Alberto Martin* (2015) Gut microbiota and colon cancer: the carbohydrate link. Molecular Cellular Oncology. Vol 2. p. 1-2
2014
S. Shalhout, D. Haddad, A. Sosin, AT. Holland, A. Al-Katib, Alberto Martin, A. Bhagwat (2014) Homeostasis in Genomic Uracil Creation and Elimination during Normal B Cell maturation, and loss of this balance during B Cell cancer development. Mol Cell Biol. Vol. 34, p. 4019-32.
K. Johnson-Henry, L. Pinnell, A. Waskow, T. Irrazabal, Alberto Martin, M. Hausner, P.M. Sherman(2014) Effects of a Short-Chain Fructo-oligosaccharide and Inulin in Caco2-bbe and C57Bl/6 Mice Models of Intestinal Injury. J. Nutrition. Vol. 144, p. 1725-33
F. Soares, I. Tattoli, M. Rahman, S. Robertson, A. Belcheva, D. Liu, C. Streutker, S. Winer, D. Winer, D. Arnoult, Alberto Martin, D. Philpott, S. Girardin (2014) The mitochondrial protein NLRX1 controls apoptotic cell death in cancer cells. J. Biol Chem. Vol. 289, p.19317-30.
A. Belcheva, T. Irrazabal, S. Robertson, C. Streutker, E. Moriyama, H. Maughan, S. Kumar, B. Green, S. Rubino, R. Pezo, W. Navarre, M. Milosevic, B. Wilson, S. Girardin, W. Edelmann, T. Wolever, D. Guttman, D. Philpott, Alberto Martin*(2014) Gut microbial metabolism fuels colorectal cancer in Msh2-deficient hosts. Cell. Vol. 158, p. 288-299.
T. Irrazábal, A. Belcheva, S. Girardin, Alberto Martin* and D. Philpott*(2014) The multifaceted role of the intestinal microbiota in colon cancer. Molecular Cell. Vol. 54, p. 309-20.
Alberto Martin*, R. Chahwan, J.Y. Parsa, M. D. Scharff* (2014) Molecular mechanism of Somatic Hypermutation. Molecular Biology of B Cells. Elsevier.
2013
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. Vol. 191, p. 5840-47.
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. Vol. 191, p. 4521-30.
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.
2012
M. Larijani* & Alberto Martin* (2012) The Biochemistry of Activation-Induced Cytidine Deaminase and its physiological functions. Seminars in Immunology. Vol. 40, p. 548-563.
H. Li, R.M. Nepal, Alberto Martin, S.A. 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, D. McCarthy, N. Simard, O. Lucia Rojas, S. Hapfelmeier, S. Rubino, S. Robertson, M. Larijani, I. Ivanov, Alberto Martin, R. Casellas, D. Philpott, S. Girardin, K. McCoy, A. Macpherson, C. Paige and J. Gommerman (2012).Acquisition of a multifunctional TNF/iNOS-producing IgA+ plasma cell phenotype in the gut. Nature. Vol. 481, p.199-203.
2011
B. Green, A, Belcheva, R.M. Nepal, B. Boulianne, and 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.
B. Duvvuri, V. Duvvuri, J. Grigull, A. Martin, Q. Pan–Hammarstrom, G.E. Wu, M. Larijani (2011). Altered spectrum of somatic hypermutation in Common Variable Immunodeficiency Disease characteristic of defective repair of AID-induced mutations. Immunogenetics. Vol. 63, p.1-11.
A. Zaheen and A. Martin (2011) Activation induced cytidine deaminase and aberrant germinal center selection in the development of humoral autoimmunities. Amer. J. of Pathology. Vol. 178, p.462-71.
2010
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
2009
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 and 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.Y. Parsa, J.L. Gommerman, A. Martin (2009). AID constrains Germinal Center size by Rendering B cells Susceptible to Apoptosis. Blood. Vol. 114, p.547-554.
* Corresponding author