Radiation induced DNA damage response
Radiation-induced clustered DNA lesions are becoming recognized as a determinant in activation of various DNA repair pathways. Clustered DNA lesions are defined as spatial clusters of various forms of direct DNA damage: base damage (BD), single strand breaks (SSBs), and double strand breaks (DSBs). Formation of radiation-induced clustered DNA lesions directly correlates with linear energy transfer (LET). Low-LET radiation, such as x-ray or high-energy proton beams, induces relatively few clustered DNA lesions. Most of the damage is caused indirectly via reactive oxygen species (ROS). These damages are repaired mainly through base excision repair (BER), SSB repair, and non-homologous end-joining repair (NHEJR).
Unlikely, high-LET radiation, such as low-energy proton and heavy ion beams (He, C, and O), is less affected by hypoxic conditions because it directly induces numerous clustered DNA lesions that have significantly slower repair kinetics and arrest cells in the G2 phase of the cell cycle. The physical proximity of clustered DNA lesions is thought to trigger cell cycle arrest and make NHEJR less efficient making cells rely more on homologous recombination repair (HRR). Thus, clustered DNA damage induced by proton and heavy ion beams make cells to rely more on HRR. To measure the efficiency of HRR and NHEJR for different types of therapeutic radiation we are using time lapsed confocal microscopy imaging of live cells in proton and heavier ion beams in conjunction with fluorescent nuclear track detectors to measure radiation at the nanoscopic scale in live cells in real time. In addition we use Monte Carlo simulations to understand how radiation energy is deposited in subcellular compartments.
Collaborators: Asaithamby Aroumougame, Ph.D., from UTSW, Steffan Greilich, Ph.D., from DKFZ, Teruaki Konishi, Ph.D., from NIRS
C.H. McFadden, T. Hallacy, D.B. Flint, D.A. Granville, A. Asaithamby, N. Sahoo, G.O. Sawakuchi, "Co-localization of DNA damage and particle tracks at the single cell level in real time," Int. J. Radiat. Oncol., Biol., Phys. 96, 221-227 (2016).
G.O. Sawakuchi, F.A. Ferreira, C.H. McFadden, T. Hallacy, D.A. Granville, N. Sahoo, M.S. Akselrod, "Nanoscale measurements of proton tracks using fluorescent nuclear track detectors," Med. Phys. 43, 2485-2490 (2016).