Dr. Kevin M. McBride
The University of Texas MD Anderson Cancer Center
Department of Molecular Carcinogenesis
The Virginia Harris Cockrell Cancer Research Center
My laboratory is located in Smithville, Texas, at UT Science Park
- Antibody repertoire development
- DNA hypermutation
- DNA damage and repair
- Single cell mutation analysis
- Protein biochemistry
- Post translational modification
- Gene targeting
Normally, DNA damage is considered detrimental to genomic stability. However, activation induced deaminase (AID) is a DNA cytidine deaminase mutator enzyme that induces hypermutation and DNA double stranded breaks (DSBs) in a beneficial manner. Without AID induced DNA lesions, B cells cannot generate mature, high affinity or isotype switched antibodies resulting in compromised immunity.
During immune responses, mature B cells diversify Immunoglobulin (Ig) genes through somatic hypermutation (SHM) and class switch recombination (CSR). SHM alters antibody affinity by introducing nucleotide changes in the antigen-binding variable region of antibodies. B cells producing antibodies with improved antigen affinity are positively selected during the process of affinity maturation. CSR is a region-specific recombination reaction that replaces one antibody-constant region with another, thereby altering antibody effector function while leaving the Ig variable region and its antigen binding specificity intact.
AID initiates SHM and CSR by programmed DNA damage at Ig loci. However, AID can also induce "off-target" DNA damage, including point mutations in oncogenes such as Bcl6 and c-myc, as well as double-stranded breaks that result in oncogenic chromosome translocations such as those between c-myc and IgH (c-myc/IgH), a hallmark of Burkitt's lymphoma. The oncogenic potential of AID therefore requires strict control to maintain genomic integrity.
In addition to lymphomagenesis, recent studies have described a widening role for AID in pathology. For example, in chronic myeloid leukemia (CML) AID action mutates ABL resulting in resistance to Imatinib, spurring pharmaceutical development of new ABL inhibitors. Furthermore, non-lymphoid AID expression has been reported under a number of pro-inflammatory or hormonally induced conditions associated with carcinogenesis. A few examples include H. Pylori infection of stomach epithelial, hepatocytes infected with hepatitis and Estrogen induction of AID in non-lymphoid tissue. Therefore, with a known role in genome destabilization and carcinogenesis, AID is a potential target for pharmaceutical intervention.
Recent studies have implicated AID and its family of deaminses (the APOBEC proteins) in removal of DNA methylation. Deamination has been proposed to demethylate DNA by a damage and repair mechanism similar to that used in SHM. The deamination of 5-mC by AID yields thymidine creating a T:G mismatch. These would be removed and repaired via base excision repair processes resulting in net removal of methylation without alteration of sequence. Short or long patch repair could trigger demethylation across multiple 5-mC resulting in net demethylation across wider regions.
1) Control of AID activity by post-translation modifications
2) Single cell analysis of AID mutations
3) Mechanism of error-prone repair in AID induced lesions
4) Role of AID in epigenetics and DNA demethylation
Gazumyan A, Timachova K, Yuen G, Di Virgilio M, Woo E, Chait BT, Nussenzweig MC, McBride KM. Amino Terminal Phosphorylation of Activation-Induced Cytidine Deaminase Suppresses c-myc-IgH translocations. Molecular & Cellular Biology (2011) Feb;31(3):442-9.
Yamane A, Resch W, Kuo N, Kuchen S, Li Z, Sun HW, Robbiani DF, McBride K, Nussenzweig MC, Casellas R. Deep-sequencing Reveals the Genomic Targets of Activation-Induced Cytidine Deaminase in B lymphocytes. Nature Immunology (2010) Jan;12(1):62-9.
Robbiani DF, Bunting S, Fledhahn N, Bothmer A, Camps J, Deroubaix S, McBride KM, Klein IA, Stone G, Eisenreich TR, Ried T, Nussenzweig A, Nussenzweig MC. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Molecular Cell (2009) Nov 25;36(4):631-41.
McBride KM, Gazumyan A, Woo EM, Schwickert TA, Chait BT, Nussenzweig MC. Regulation of class switch recombination and somatic mutation by AID phosphorylation. J Exp Med (2008) Oct 27;205(11):2585-94.
Dorsett Y, McBride KM, Jankovic M, Gazumyan A, Thai TH, Robbiani DF, Di Virgilio M, San-Martin BR, Heidkamp G, Schwickert TA, Eisenreich T, Rajewsky K, Nussenzweig MC. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity (2008) May;28(5):630-8.