Synthetic LEThality.

What’s more important, physics or biology? Protons have a relative biological effectiveness (RBE) of 1.1 compared to photons. Because of their higher linear energy transfer (LET), protons produce more clustered radiation damage, which is thought to result in slightly more effective cell kill. But how do DNA repair defects play into all this? In this study, cells with defects in the two major DNA repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR), were subjected to photon radiation and increasing energy (and LET) proton radiation. The overwhelming determinant of radiation sensitivity was DNA repair deficiency—not radiation quality. In particular, NHEJ was the dominant force in repairing radiation damage. As a result, defects in NHEJ sensitize cells regardless of radiation quality. However, the authors interestingly found that the role of HR became more prominent in repairing damage from higher LET radiation (i.e. high energy protons). As a result, cells with germline BRCA1 mutations (an important player in HR) were more sensitive to higher energy protons than to either lower energy protons or photons. TBL: Defects in homologous recombination (including BRCA1 mutations) result in a relative increase in cell sensitivity to high LET protons compared to photons. | Bright, Int J Radiat Oncol Biol Phys 2019