Our research focus has been on the biology of the DNA-dependent protein kinase (DNA-PK), composed of the DNA-binding Ku70/80 heterodimer and the large catalytic subunit DNA-PKcs, the key regulator of the non-homolog end-joining (NHEJ) pathway for DNA double-strand break (DSB) repair. DSBs generated by radiation exposure, byproducts of oxidative metabolism, and chemotherapeutic drugs are the most deleterious form of DNA damage. Unattended or dysregulated DSBs would otherwise lead to cell death, mutagenesis, genomic instability, and cancer formation.
DSBs are primarily repaired by the NHEJ and homologous recombination (HR) repair pathways. While NHEJ is active throughout the cell cycle phases and is the predominant DSB repair mechanism in mammals, HR requires an intact identical template for DSB repair and is active during the S/G2 phases. DNA-PKcs and the NHEJ pathway are also essential for v(d)j recombination during T- and B-cell lymphocyte development. Thus, deficiency in DNA-PKcs activity results in a severe combined immunodeficiency (SCID) phenotype in mammals.
Our goal is to further delineate the mechanisms of DNA-PKcs in DNA damage repair, cell cycle checkpoints, chromosomal stability maintenance, and carcinogenesis. Knowledge gained will be employed to improve radiation therapy as cancer treatment.