University of Chicago :: Department of Pathology ::

Quick Links

Karen Frank, MD, PhD

Assistant Professor
Associate Residency Director

Contact

University of Chicago
5841 S. Maryland Ave.
AMB Rm P311, MC0001
Chicago, IL 60637
Phone: (773) 834-7407
Fax: (773) 702-2315
Lab: (773) 834-7930
Lab: AMB Room G320
kfrank@uchicago.edu

Education

B.S., Pennsylvania State University (Biochemistry)
M.D., Ph.D., University of Pennsylvania (Medicine/Biochemistry)
Postdoctoral Research, Harvard University

Committee Membership

Committee on Immunology
Committee on Cancer Biology
Committee on Genetics
Committee on Molecular Medicine

Research Interests

V(D)J Recombination and DNA Repair
V(D)J recombination is a tightly regulated DNA rearrangement process required to generate a specific immune response through the creation of diverse antigen receptors. The antigen-specific region of the receptor is generated by the assembly of composite gene segments using a site-directed, non-homologous recombination reaction. V(D)J recombination is initiated by the lymphoid-specific RAG endonuclease by the generation of specific double-strand breaks. Next, the nonhomologous DNA end joining (NHEJ) pathway is utilized to complete the V(D)J recombination process.

Nonhomologous End Joining
The NHEJ pathway is not specific to the V(D)J recombination pathway, but is one of the major pathways of DNA repair. DNA in any cell, not just blood cells, can be damaged from exposure to radiation or environmental chemicals, or from the by-products of metabolism. These DNA breaks are potentially harmful to the cell and must be repaired for the cell to survive. Five proteins in this pathway have been identified, including the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the Ku70/80 heterodimer (Ku), and the XRCC4 and DNA ligase IV proteins. XRCC4 and DNA ligase IV form a complex to complete the final ligation step of the repair process.

Deficiencies of Proteins in the NHEJ Pathway
Deficiencies of Ku 70, Ku 80, XRCC4, or DNA ligase IV lead to a similar phenotype, including growth defects, premature senescence, sensitivity to ionizing radiation, and defective V(D)J recombination. Deficiency of either XRCC4 or DNA ligase IV in mice also causes embryonic lethality. The mutant embryos exhibit defective neurogenesis manifested by extensive apoptosis of newly generated postmitotic neurons. Our findings demonstrate that differentiating lymphocytes and neurons strictly require the XRCC4 and DNA ligase IV end-joining proteins, and point to the general stage of neuronal development in which these proteins are necessary. Studies involving the cross of DNA ligase IV-deficient mice with p53-deficient mice (a cancer prone mouse strain), demonstrated that the ligase IV deficiency shortened the latency of tumor development and changed the type of lymphoma that the mice develop.

Association of V(D)J Recombination and NHEJ with Human Disease
Genetic defects in factors involved in this pathway can lead to severe immunodeficiency, resulting in an inability to fight infections. Errors in the V(D)J recombination mechanism can lead to chromosomal rearrangements that lead to cancer. Also, defects in NHEJ are associated with genetic instability which has been associated with cancer development.

Research Questions Related to V(D)J Recombination and Nonhomologous End Joining
Are there additional proteins involved in the NHEJ complex? How do the known proteins interact with one another? What is the role of the BRCT (BRCA1 C-terminal homology) domains of DNA ligase IV in these interactions? How are the XRCC4 and DNA ligase IV proteins regulated during this process?

Selected Publications

Woo, L.L., Futami, K., Simamoto, A., Furuichi, Y., and Frank, K.M., The Rothmund-Thomson Gene Product, RECQL4, Localizes to the Nucleolus in Response to Oxidative Stress. Exp. Cell Res. In press.
Foster, R.E, Nnakwe, C, Woo, L, and Frank, K.M., Monoubiquitination of the nonhomologous end joining protein XRCC4. Biochem Biophys Res Commun. 341:175-183, 2006.
Wang YG, Nnakwe C, Lane WS, Modesti M, Frank KM., Phosphorylation and regulation of DNA ligase IV stability by DNA-dependent protein kinase. J Biol Chem. 279:37282-90, 2004.
Sekiguchi, J., Ferguson, D. O., Chen, H. T., Yang, E. M., Earle, J., Frank, K., Whitlow, S., Gu, Y., Xu, Y., Nussenzweig, A., and Alt, F. W., Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development. Proc. Natl. Acad. Sci. U.S.A. 98:3243-3248, 2001.
Sharpless, N. E., Ferguson, D. O., O’Hagan, R. C., Castrillon, D. H., Lee, C., Farazi, P. A., Alson, S., Fleming, J., Morton, C. C., Frank, K., Chin, L., Alt, F. W., and DePinho, R. A., Impaired non-homologous end joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions. Mol. Cell 8:1187-1196, 2001
*Frank, K. M., *Sharpless, N. E., Gao, Y., Sekiguchi, J. M., Ferguson, D. O., Zhu, C., Manis, J. P., Horner, J., DePinho, R. A., and Alt, F. W. DNA ligase IV-deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Molec. Cell, 5:993-1002, 2000. *These authors contributed equally.
Ferguson, D. O., Sekiguchi, J. M., Chang, S., Frank, K. M., Gao, Y., DePinho, R. A., and Alt, F. W. The non-homologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc. Natl. Acad. Sci. USA, 97:6630-6633, 2000.
Gao, Y., Ferguson, D. O., Xie, W., Manis, J. P., Sekiguchi, J., Frank, K. M., Chaudhuri, J., Horner, J., DePinho, R. A., and Alt, F. W. Interplay of p53 and DNA-repair protein XRCC4 in tumourigenesis, genomic stability and development. Nature, 404:897-900, 2000.

View all publications