Biochemistry and Biophysics
Area of interest
The end-joining pathway has an important role in all cell types repairing DSBs caused by DNA damaging agents (e.g. ionizing radiation, certain chemotherapeutic drugs). End joining is also essential for efficient resolution of DSB intermediates during V(D)J recombination, a lymphocyte specific process required for assembly of the immune system’s antigen specific receptors. Defective end joining thus results in radiation sensitivity, severe immunodeficiency, age-dependent failure of stem cells, and an increased incidence of cancer. My lab uses diverse molecular biological approaches to develop an understanding how end joining works, and what happens when it doesnt.
Awards and Honors
We were the first to link several newly described DNA polymerases to NHEJ, and then showed how three different DNA polymerases make unique contributions to this pathway. They have varying substrate requirements that dictated their biological roles, and additionally have varying affinity for the NHEJ holoenzyme, ensuring a hierarchy of recruitment. We have additionally collaborated with several other groups in the research triangle area (Drs Kunkel, Pederson, and London, NIEHS; Dr. Lee, UNC) to clarify the structural basis for these differing biochemical characteristics.
We determined another component of NHEJ, Ku, has several unanticipated functions. We first determined it is sufficient for a kind of ?passive? chromatin remodeling: it peels DNA off the surface of nucleosomes without the typical requirement for ATP hydrolysis. More recently we characterized Ku as an enzyme. It is an AP lyase, and helps process damaged ends expected in the course of chromosome break repair. It is surprisingly one of the primary sources of AP lyase activity in cell extracts, and is uniquely active on its expected biological substrate (double strand breaks).
Dale Ramsden has received a Searle Scholarship and a Jefferson Pilot award and is currently a Leukemia and Lymphoma Society Scholar.