Research Unit in Mechanisms of Genetic Diversity



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Antibodies are produced by B lymphocytes. During an infection or after vaccination, antigen-specific B lymphocytes form specialized structures known as germinal centers, where they turn on mutagenic mechanisms to remodel the immunoglobulin genes encoding for the antibody light and heavy chain. 

TwoModified from 1IGY mechanisms - somatic hypermutation (SHM) and immunoglobulin gene conversion (IgGC) - can change the sequence of the VARIABLE region of the antibody, which recognizes the antigen.

The diversification of the Variable region by programmed mutation is coupled to a process by which the antibody variants with the highest affinity for the antigen are selected by Darwinian competition. This iterative cycle of mutation and selection happens within the unique anatomical structure of the germinal centers in lymphoid tissues, and permits the improvement of antibody response a few days after the first exposure to the antigen and the generation of immunological memory.

A third mechanism - class switch recombination (CSR) - exchanges the default "CONSTANT" region of the antibody heavy chain that defines the IgM class for another one, to produce IgG, IgE or IgA. Each antibody class specializes in eliminating different antigens by mediating specific interactions with immune cells and soluble factors.

SHM, IgGC and CSR are initiated by the deamination of cytosine bases in DNA to uracil by the enzyme Activation Induced Deaminase (AID). Defects in any of these mechanisms cause immunodeficiency.

AID is a unique enzyme because it directly mutates the self-genome to fulfill its biological role. Unfortunately, AID causes collateral damage in the form of genomic mutations and chromosomal translocations that predispose to cancer such as B cell lymphoma and leukemia. 

We investigate : 
  • The mechanisms regulating the mutagenic activity of AID and their impact on the efficiency of the antibody response and on preventing oncogenic outcomes.
  • The interplay between AID and DNA repair to protect B cells in the germinal center, as they proliferate in the presence of DNA damage.
We use structure-function, biochemistry, cell biology and genetics to study the regulation of AID and its interplay with DNA repair pathways. We also use mouse models with deficiencies in key components of the pathways involved in SHM and CSR. 

We have discovered several mechanisms regulating AID protein stability and localization, as well as a link between AID and DNA repair during class switch recombination. We have also exhaustively analyzed the role of the DNA repair enzyme uracil-DNA glycosylase UNG during the germinal center response, in the mechanisms of antibody diversification and in modulating the oncogenic effects of AID.


    Contact

    Dr Javier M Di Noia

    110 Av des Pins Ouest

    H2W 1R7, Montréal, Québec, Canada

    javier.di.noia@ircm.qc.ca


Motivated students seeking to pursue MSc or PhD should send a letter of motivation, CV and university transcripts demonstrating excellent academic records. Graduate students can register at either Université de Montréal or McGill University.

Post-docs candidates should submit a letter of motivation suggesting a project proposal, and full CV that includes publications, technical skills and academic achievements, as well as names of references.

Please email javier.di.noia(at)ircm.qc.ca 
















 

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