Research

1. DNA recombination and DNA repair

2. Transcription and regulation of gene expression

3. Chromosomal translocations and genomic instability

My lab studies immunoglublin gene rearrangements. Mammalian immune system utilizes DNA recombination as a means to create antigen receptor diversity. This includes the site-directed V(D)J recombination that assembles the antigen binding domain of the immunoglobulin (Ig) and T cell receptor genes; and a regional-specific class switch recombination (CSR) that changes the constant region of the immunoglobulin. Both events involve DNA double strand break intermediates that, if not repaired properly, can cause chromosomal translocations.

CSR happens in antigen-stimulated B cells that allows Ig isotype switching from IgM/IgD to IgG, IgA or IgE. Failure of CSR leads to hyperIgM syndrome. Dysregulation of CSR contributes to oncogenic chromosomal translocations frequently observed in a large number of lymphomas. CSR is directed by large repetitive DNA regions (2~12kb) that lack extensive homology or conserved signal sequence. An independent process also occurring in stimulated B cells is somatic hypermutation (SHM), which mutates the Ig variable region to allow antibody affinity maturation. Like CSR, defective SHM leads to immunodeficiency, and aberrant targeting of SHM to non-Ig genes can cause oncogene mutations and chromosomal translocations in various types of B cell malignancies. Both CSR and SHM are initiated by a lymphoid specific factor called activation-induced cytidine deaminase (AID). AID is a small protein that shares homology to a large family of cytidine deaminases. Members of this family have diverse functions in RNA editing, gene conversion, Ig diversification, and host defense against retroviral infections.

We are currently focusing on studying: (1) the targeting mechanism and regulation of AID. (2) the mechanism of generating DNA breaks at switch regions during B cells class switch recombination. (3) the repair of switch region DNA breaks and their involvement in oncogenic translocations.

Representative Publications

Han, L and Yu, K. (2008) Altered kinetics of NHEJ and CSR in ligase IV-deficient B cells.  Journal of Experimental Medicine. (in press)

Yu, K., Chedin, F., Hsieh, C. L., Wilson, T. E. and M. R. Lieber. (2003). R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nature Immunology 4: 442-451.

Yu, K., Huang FT. and M. R. Lieber. (2004). DNA substrate length and surrounding sequence affect the activation-induced deaminase activity at cytidine. J. Biol. Chem. 279: 6496-6500.

Yu, K., Roy D., Bayramyan M., Haworth I. S., and M. R. Lieber. (2005). Finestructural analysis of activation-induced deaminase accessibility to class switch region R-loops. Mol. Cell. Biol. 25(5): 1730-1736.

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