Section: Research

Janet Stavnezer, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Molecular Genetics and Microbiology

Other Affiliation(s):
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Mechanism and Regulation of Antibody Class Switch Recombination

B cells respond to immunization or infection by diversifying the antibodies they produce through two processes: antibody class switch recombination and somatic hypermutation of their antigen-binding regions. Switch recombination causes a change in antibody class expression from IgM to IgG, IgA or IgE, resulting in an increased ability of the antibody to remove the pathogen. Somatic hypermutation, in conjunction with B cell selection, results in increases in the antigen binding ability of the antibody.

Both class switch recombination and somatic hypermutation are initiated by the enzyme activation induced cytidine deaminase (AID) acting on the antibody genes. After AID acts, two different DNA repair pathways begin to attempt to repair the resulting dU bases. These repair processes introduce DNA breaks and mutations that lead to class switch recombination and mutation of the variable region genes. The figure below diagrams the process of class switch recombination.

Our data demonstrate that enzymes in the base excision repair pathway are required for introducing the DNA breaks at the sites of the dU bases.  We have also shown that several proteins in the mismatch repair pathway are involved in class switching. Our results indicate that mismatch repair proteins convert single-strand breaks introduced by the base excision repair pathway to the double-strand breaks that are necessary for switch recombination. In other genes, these repair processes would seal up the DNA breaks introduced when dUs are accidentally introduced, but our data suggest that during class switching these DNA repair processes are overwhelmed by the large numbers of dU bases introduced by AID.  We are investigating this hypothesis further.

Sometimes DNA breaks instigated by AID lead to aberrant recombination events that result in malignant transformation and B cell lymphoma. We are investigating what genes are required for correct class switch recombination, and whether AID introduces DNA breaks at other sites in the genome that can be involved in aberrant recombination events. We are also investigating the role of the tumor suppressor p53 in regulating class switching.

Office: S5-109
Phone: 508-856-4100
E-mail: Janet.Stavnezer@umassmed.edu
Keywords: Immunology, DNA Recombination, Mouse Models, Gene Regulation, DNA Repair

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