XRCC4 AND V<D>J RECOMBINATION AND DNA REPAIR

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DESCRIPTION: a. Candidate: Dr. Karen M. Frank received her M.D. and Ph.D. degrees from the University of Pennsylvania in 1994. She has been a clinical pathology resident and research fellow at Brigham and Women's Hospital and Children's Hospital since 1994. She served as Chief Resident in clinical pathology at Brigham and Women's Hospital from January 1996 to June 1996. Dr. Frank listed six published papers, in which she was first author on four. The candidate's goal is to perform immunology research at a major medical center with an academic faculty appointment, and with a joint appointment in a tertiary care hospital. b. Mentor: Dr. Frederick Alt is the Charles Janeway Professor of Pediatrics and Professor of Genetics and Pediatrics at the Harvard Medical School, and an Investigator of the Howard Hughes Medical Institute at the Children's Hospital. c. Career Development Plan: The candidate will devote 85-90 percent time to research. She will learn new techniques in molecular biology, increase her knowledge of immunology, and develop skills in experimental design and presentation of research results. A modest amount of time will be devoted to teaching and to learning to manage a laboratory. d. Research Plan: Dr. Frank proposes to investigate the function of the newly cloned gene XRCC4 in the V(D)J recombination process. XRCC4 was isolated in the mentor's laboratory on the basis of its potential involvement in V(D)J recombination and double stranded (DS) DNA break repair. The hypothesis of the project is that the XRCC4 protein plays a direct role in the V(D)J recombination process. Three approaches will be used to address the hypothesis. In Specific Aim 1, Dr. Frank will attempt to determine functional domains of XRCC4 by mutational analysis and by examining the evolutionary conservation of amino acid sequence. Dr. Frank will also try to determine if XRCC4 is phosphorylated and whether phosphorylation has any role in its function. In Specific Aim 2, Dr. Frank proposes to investigate whether XRCC4 associates with known V(D)J recombination components such as RAG-1, RAG-2, Ku 80, Ku 70 and DNA-PKCS and other newly discovered proteins. In Specific Aim 3, Dr. Frank will generate XRCC4 knockout (KO) mice and study the role of XRCC4 in lymphocyte development and in DNA repair. e. Environment and Institutional Support: The training will take place in Dr. Alt's laboratory in the Enders Research Building of the Children's Hospital.