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Les Hanakahi, Ph.D.Joanna Burdette

Assistant Professor
Department of Medicinal Chemistry and Pharmacognosy

University of Illinois College of Pharmacy at Rockford
1601 Parkview Avenue
Rockford, IL 61107-1822

Office: N-301
Office Phone: 815-395-5924
Lab: N-320
E-mail address: hanakahi@uic.edu

Education:

Imperial Cancer Center Research Fund, Clare Hall Laboratories, South Mimms, England, Post-Doctoral Fellow 1999-2002
Yale University, New Haven, CT, Post-Doctoral Fellow 1997-1998
Yale University, New Haven, CT, PhD Molecular Biophysics and Biochemistry 1996
University of Hawaii, Honolulu, HI, BS Biology (with honors) 1990

Research Interests:

Cancer is caused by mutations or changes in the genetic information (genes) contained within every cell.  A contributing source of mutations in human cells is the DNA Double-Strand Break (DSB).  When both strands of DNA are physically broken (a DSB), several things can happen.  These potential outcomes can be ordered in increasing severity as: i) degradation of DNA ends exposed by the break resulting in the loss of small amounts of genomic information, ii) loss of DNA segments resulting in the loss of large amounts of genomic information or iii) the relocation of DNA segments resulting in gross changes in genomic structure.

The major pathway for DSB repair in human cells is Non-Homologous End Joining (NHEJ) ­– a repair process in which DNA ends that share no sequence homology (DNA sequence identity) are rejoined to restore the integrity of the genome. The primary focus of my research is to understand, in molecular detail, how DNA ends that are exposed by a DSB are recognized, protected from degradation and efficiently re-joined in human cells.

Much of the research being done in my lab centers on the participation of a small molecule, inositol hexakisphosphate (IP6), in the repair of DSBs by mammalian NHEJ. We have found that IP6 is bound by an NHEJ factor and stimulates NHEJ in vitro. This finding opened new possibilities for investigating the molecular mechanism of NHEJ and exciting new avenues for pharmaceutical control of NHEJ in human cells.

The discovery that IP6 stimulates mammalian NHEJ in vitro suggests the exciting possibility that synthetic or natural products resembling IP6 may be used to control the efficiency of NHEJ in human cells.  An example of the utility of such IP6-analogs is reduction of NHEJ efficiency in tumor cells could to augment traditional radiation therapy by preventing DSB repair in cancer cells.  This would decrease tumor cell viability and promote reductions in tumor mass.

Selected Publications (from 23 total):

  1. Jayaram, S, Gilson, T. Ketner, G and Hanakahi, L.A. 2008. E1b 55k-independent destabilization of the DNA ligase IV-XRCC4-XLF complex by E4 34k during adenovirus infection. Virology. 382, 163-170.
  2. Jayaram, S., Ketner G. Adachi, N. and Hanakahi, L.A. 2008. Loss of DNA Ligase IV prevents recognition of DNA double-strand break repair proteins XRCC4 and XLF. Nucleic Acids Res. 36, 5773-5786.
  3. Cheung, J.C.Y., Salerno, B. and Hanakahi, L.A. 2008. Evidence for an inositol hexakisphosphate role for Ku in mammalian NHEJ that is independent of its role in the DNA-dependent protein kinase. Nucleic Acids Res. 36, 5713-5726.
  4. McGregor-Mason, T., Smeaton, M., Cheung, J., Hanakahi, L.A. and Miller, P. 2008. 3'- Terminal Methylphosphonates Disrupt Binding of Ku70/80 to Linear DNA Duplexes and Enhance NER-Mediated Excision. Bioconjugate Chemistry. 19, 1064-1070.
  5. Smeaton, M.B., Miller, P.S., Ketner, G. and Hanakahi, L.A. 2007. Small-scale extracts for the study of nucleotide excision repair and non-homologous end joining. Nucleic Acids Research. 35, e152.
  6. Baker, A., Rohleder, K.J., Hanakahi, L.A. and Ketner, G. 2007. The adenovirus E4 34k and E1b 55k oncoproteins target host DNA ligase IV for proteasomal degradation. J. Virol. 81, 7034-7040.
  7. Rubin, E., Wu, X., Zhu, T., Cheung, J., Chen, H., Lorincz, A., Pandita, R., Sharma, G., Ha, H., Gasson, J., Hanakahi, L.A., Pandita, T., and Sukumar, S. 2007. A role for the HOXB7 homeodomain protein in DNA repair. Cancer Research. 67, 1527-1535.
  8. Hanakahi, L.A., 2006. 2-step purification of the Ku DNA repair protein expressed in Escherichia coli. Protein Expression and Purification 52, 139-145.
  9. Cocco, M.J., Hanakahi, L.A., Huber, M.D. and Maizels, N. 2003. Distamycin binds G4 DNA and maps the interaction surface for nucleolin RGG domain recognition. Nucleic Acids Research. 31, 2944-2951.
  10. Dai, Y., Kysela, B., Hanakahi, L.A., Manolis, K., Riballo, E., Stumm, M., Harville, T.O., West, S.C., Oettinger, M.A. and Jeggo, P.A. 2003. Nonhomologous end joining and V(D)J recombination require an additional factor. Proc. Natl. Acad. Sci. USA. 100,
    2462-2467.
  11. Hanakahi, L.A. and West, S.C. 2002. Specific interaction of IP6 with human Ku70/80, the DNA-binding subunit of DNA-PK. EMBO J. 21, 2038-2044.
  12. Hanakahi, L., Bu, Z. and Maizels, N. 2000. The C-terminal Domain of Nucleolin Accelerates Nucleic Acid Annealing. Biochemistry. 39, 15493-15499.
    corresponding author
  13. Hanakahi, L.A., Bartlet-Jones, M., Chappell, C., Pappin, D. and West, S.C. 2000. Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair. Cell. 102, 721-729.
  14. Yu, V.P., Koehler, M., Steinlein, C., Schmid, M., Hanakahi, L.A., van Gool, A.J., West, S.C. and Venkitaraman, A.R. 2000. Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev. 14, 1400-1406.
  15. Hanakahi, L.A. and Maizels, N. 2000. Transcriptional activation by LR1 at the Emu enhancer and switch region sites. Nucleic Acids Research. 28, 2651-2657.
  16. West, S.C., Chappell, C., Hanakahi, L.A., Masson, J.-Y., McIlwraith, M.J. and Van Dyck, E. 2000. Double-strand break repair in human cells. Cold Spr. Harb. Symp. Quant. Biol. 65, 315-321.
  17. Hanakahi, L.A., Sun, H. and Maizels, N. 1999. High affinity interactions of nucleolin with G-G-paired rDNA. J. Biol. Chem. 274, 15908-15912.
  18. Dempsey, L.A., Sun, H., Hanakahi, L.A. and Maizels, N. 1999. G4 DNA binding by LR1 and its subunits, nucleolin and hnRNP D, A role for G-G pairing in immunoglobulin switch recombination. J. Biol. Chem. 274, 1066-1071.
  19. Dempsey*, L.A., Hanakahi*, L.A. and Maizels, N. 1998. A specific isoform of hnRNP D interacts with DNA in the LR1 heterodimer: canonical RNA binding motifs in a sequence-specific duplex DNA binding protein. J. Biol. Chem. 273, 29224-29229.
    *contributed equally to this work.
  20. Hanakahi, L.A., Dempsey, L.A., Li, M.-J. and Maizels, N. 1997. Nucleolin is one component of the B cell-specific transcription factor and switch region binding protein, LR1. Proc. Natl. Acad. Sci. USA. 94, 3605-3610.
  21. Williams, M., Hanakahi, L.A., and Maizels, N. 1993. Purification and properties of LR1, an inducible DNA binding protein from mammalian B lymphocytes. J. Biol. Chem. 268, 13731-13737.
  22. Hokama, Y., Honda, S.A.A., Hanakahi, L.A., and Terada, K.Y. 1988. C-reactive protein (CRP) and Platelet Activating Factor (PAF)-CRP complexes induce production and release of Interleukin-1 by human monocytes. J. Clin. Lab. Anal. 2, 155-160.

 

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