During the initial stages of the immune response against foreign antigens, a vast array of receptors expressed on the surface of B and T cells recognize and bind the myriad of foreign molecules. Diversity amongst the genes encoding the recognition regions of antigen receptors is generated through V(D)J recombination, a process in which individual V, D, and J gene segments are rearranged. Two types of activities are required for V(D)J recombination; lymphoid-specific factors, such as recombination activating genes 1 and 2 (RAG1/2), and the ubiquitously expressed non-homologous end-joining (NHEJ) DNA repair factors, such as Artemis. Mutations in Artemis are known to cause a human severe combined immunodeficiency syndrome associated with cellular radiosensitivity (RS-SCID). Recent evidence suggests that hypomorphic mutations in Artemis may also predispose to lymphoma in human patients. Artemis, a 76 kDa protein, possesses single strand 5' to 3' exonuclease activity and acquires endonucleolytic activity upon interaction with and phosphorylation by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). In addition to its role in V(D)J recombination, Artemis is also required for general DNA double strand break repair (DSB) and suppressing chromosomal aberrations, including translocations and telomeric fusions. It is not yet known whether both exo- and endonucleolytic activities or regulation by DNA-PKcs are required for each of the multiple functions of Artemis, nor is it clear what impact the Artemis mutations found in human patients have on its intrinsic biochemical activities. Thus, the goals of the specific aims described in this proposal are to use combined biochemical, cellular and genetic approaches to further elucidate the catalytic repertoire and in vivo roles of Artemis. These studies will provide a more clear understanding of the functions of Artemis in DNA repair processes and insights into the molecular mechanisms underlying immune system defects and predisposition to lymphoid malignancies in human patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - B (CMI)
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Nasseri, M Faraz
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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