Our Science – Nussenzweig Website

Andre Nussenzweig, Ph.D.

Experimental Immunology Branch Head, Molecular Recombination Section Senior Investigator Building 10, Room 4B04 10 Center Drive Bethesda, MD 20892 Phone:   301-435-6425 Fax:   301-496-0887 E-Mail:   andre_nussenzweig@nih.gov

Biography

Dr. Nussenzweig received his Ph.D. from the Department of Physics at Yale University. He obtained postdoctoral training at the Ecole Normale Superieure in Paris and at Memorial Sloan-Kettering Cancer Center before joining the Experimental Immunology Branch.

Research

Mechanisms of DNA, Damage Detection and Repair in Lymphocytes

The focus of this group is to understand the mechanisms by which cells monitor and repair DNA double-strand breaks (DSBs). DSBs are generated spontaneously by reactive byproducts of oxygen metabolism during DNA replication and exposure to ionizing radiation. DSBs also serve to initiate a number of recombination events such as meiotic recombination and antigen receptor gene rearrangements in lymphocytes. While our research has addressed processes that are utilized by all cell types, we are particularly interested in how immune cells have adapted DNA damage detection and repair systems for their unique requirements.

Chromosomal DNA is continually broken and repaired during lymphocyte development in order to diversify the germline repertoire. Genes encoding variable regions of antigen receptors are assembled in immature B and T cells by a site-specific recombination reaction referred to as V(D)J recombination. During an immune response, mature B cells undergo further alterations of functionally rearranged immunoglobulin genes by class-switch recombination and somatic mutation, both of which involve DNA DSB intermediates. The fidelity of DNA breakage and rejoining events during these chromosomal rearrangements is critical for maintaining genomic stability as oncogenic translocations may result from aberrations in physiological recombination.

Mammalian cells have evolved several DNA repair mechanisms to counteract the deleterious effects of DSBs, including homologous recombination and nonhomologous end joining. Recently, our group has shown that components of the nonhomologous end-joining pathway, which repair breaks during V(D)J and class-switch recombination, are caretaker genes that maintain the integrity of the genome. Mice lacking both a nonhomologous end-joining protein (Ku80 or Ku70) and the p53 tumor suppressor protein develop pro-B cell lymphomas at an early age that result from a specific set of chromosomal translocations and gene amplifications involving IgH and c-myc, reminiscent of Burkitt's lymphoma. We are currently studying the mechanisms by which oncogenic translocations are generated in the absence of nonhomologous end joining. We are also characterizing proteins that mediate DNA damage detection and signaling functions during V(D)J and class-switch recombination using molecular approaches including targeted gene inactivation and transgenic mice. Overall, the goal of these experiments is to elucidate the mechanisms by which DNA damage detection, signaling, and repair are integrated during lymphocyte development and activation.

This page was last updated on 6/11/2008.