The repair of Double Strand Breaks (DSB) is central to the maintenance of genomic integrity. The importance of DSB repair is highlighted by the fact that failure to repair a double strand break can result in the loss of genetic information or genetic rearrangements that can lead to carcinogenesis. Repair of DSBs can be effected either by Homologous Recombination or by Non-Homologous End-Joining (NHEJ). Homologous recombination utilizes a sister duplex to restore genetic information lost at the site of a DSB. NHEJ, as its name implies, is a homology independent process and represents an important pathway employed by human cells in DSB repair. The primary focus of my research is to understand, in molecular detail, how exposed DNA ends are recognized, protected from degradation and efficiently re-joined by the mammalian NHEJ apparatus.

While several of the factors required for NHEJ in human cells have been identified, in vitro reconstitution of the mammalian NHEJ reaction has not yet been achieved. One aspect of my research is to use a combination of genetic and biochemical approaches to identify and characterise additional components that are required for efficient NHEJ in mammalian cells.

Of particular interest is the role of inositol polyphosphates (InsP) in the human NHEJ reaction. InsPs are the multiply phosphorylated forms of the 6-carbon inositol ring. We had previously reported that these small molecules can act as stimulators of NHEJ in vitro and have determined that at least one of the factors participating in NHEJ is capable of specifically binding InsPs. I would like to extend these findings and study the effects of InsPs on NHEJ in vivo, and examine the molecular mechanism of NHEJ stimulation by InsPs. Characterization of the specific role played by small molecule effectors of the mammalian NHEJ reaction may have application in areas such as gene therapy, gene targeting and drug design.

Biochemistry and molecular biology, Non-Homologous End-Joining (NHEJ), DNA double strand break repair, inositol phosphate, Ku, DNA-PK, XRCC4, DNA Ligase IV

Research Fellowships and Awards:

2004

- Tech transfer Seed Grant Award

- Faculty Research Initiatives Award

- Faculty innovation Fund, Yang Memorial Scholar

- Maryland Cigarette restitution Fund Award

2003 Rita Allen Foundation Scholar's Award

1999 Human Frontier Science Program (HFSP) Post-Doctoral Fellowship

1997 Ford Foundation Post-Doctoral Fellowship

1993 NIH MARC Pre-Doctoral Fellowship

1990 NSF Minority Graduate Fellowship

Professional Service:

Ongoing Minority Access to Research Careers (MARC), University of Hawaii, returning alumni lecturer.

2006 Women Serious About Science – Baltimore Polytech guest speaker

2004 Baltimore Area DNA Repair Symposium organizer

1997 Summerbridge New Haven Summer Program academic volunteer.

1996 Yale Graduate Student Research Symposium (GSRS). Co-Chair and Head of Fund-raising.

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.

Chappell, C., Hanakahi, L.A., Karimi-Busheri, F., Weinfeld, M. and West, S.C. 2002. Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining. EMBO J., 21, 1-6.

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.

West, S.C., Chappell, C., Hanakahi, L.A., Masson, J.-Y., McIlwraith, M.J., Van Dyck, E. 2000. Double-strand break repair in human cells. Cold Spr. Harb. Symp. Quant. Biol. 65, 315-321.