Research Interest -

 Deficiencies in DNA-damage signaling and repair pathways are fundamental to the etiology of most human cancers.  Of the many types of DNA damage that occur within the cell, DNA double-strand breaks (DSBs) are particularly dangerous.  DSBs are caused by both endogenous and exogenous threats. An inability to respond properly to DSBs or to repair them correctly can lead to cell death or promote tumorigenesis.  Our research is focused on the mechanisms by which cells recognize, respond to, and repair of Ionizing radiation induced DSBs. We are motivated by the fact that a more complete understanding of these pathways will provide insights into how cancer is triggered, and may lead to the development of more effective cancer therapies.

Eukaryotic cells have evolved into distinct mechanisms for repairing DSBs: homologous recombination (HR) and non-homologous end joining (NHEJ).  These mechanisms differ primarily in that HR requires a homologous DNA template, while NHEJ acts independently of homologous DNA. The majority of my research focuses on the NHEJ repair pathway.  The DNA dependent protein kinase (DNA-PK) complex, consisting of the DNA-binding subunit Ku and the catalytic subunit DNA-PKcs, are central to NHEJ repair. Utilizing transgenic mouse models, we demonstrated that while the kinase activity of DNA-PKcs is absolutely essential for the repair of DNA DSBs.  Although it has been established for many years that the kinase activity of DNA-PK is stimulated by DNA damage, the biologically relevant substrates of DNA-PK have remained elusive.  We have recently identified WRN as a biologically relevant substrate for SNA-PK. We have further shown that DNA-PK assembles into a complex on DNA with WRN protein and regulates WRN activities. WRN deficiency is causative in a human disease characterized by premature aging and increased incidence of cancer.  These studies suggest a link between the DNA repair and aging processes.  Very recently, we demonstrated that DNA-Pkcs is autophosphorylated in response to DNA damage and that this very early event is essential for the repair of DSBs.  In addition, we demonstrated, for the first time, the localization of DNA-PKcs at the sites of DNA damage in vivo. We are also investigating how some of the proteins involved in NHEJ control other processes such as telomere maintenance.  Telomere maintenance is a critical component of cellular senescence, telomerase is activated in most cancers, and telomere dysfunction may be an early event causing genomic instability during the progression of certain cancers. Recently, we discovered that Ku is associated with the mammalian telomere and the Ku functions in a unique way at the telomere to prevent end joining.  Using a transgenic mouse model we have recently determined that the DNA-PKcs kinase domain is critical for telomere capping and we are in the process of identifying specific telomere proteins that are phosphorylated by DNA-PKcs in vivo.

A cell's ability to repair damaged DNA is critical, not only for the prevention of malignancy, but also for the resistance of many tumors to current therapies.  Understanding DNA repair processes and cellular radiation responses in general will therefore help to improve the efficiency of radiation treatment and to protect the normal tissues during radiation therapy.  In this respect, we are also interested in studying radiation responses in tumor and normal cells with the objective to improve radiation therapy and cancer treatment in general.