Molecular Mechanisms of Specific Cellular DNA Damage Response and Repair Induced by the Mixed Radiation Field During Boron Neutron Capture Therapy

Abstract

The impact of a mixed neutron-gamma beam on the activation of DNA damage response (DDR) proteins and non-coding RNAs (ncRNAs) is poorly understood. Ionizing radiation is characterized by its biological effectiveness and is related to linear energy transfer (LET). Neutron-gamma mixed beam used in boron neutron capture therapy (BNCT) can induce another type of DNA damage such as clustered DNA or multiple damaged sites, as indicated for high LET particles, such as alpha particles, carbon ions, and protons. We speculate that after exposure to a mixed radiation field, the repair capacity might reduce, leading to unrepaired complex DNA damage for a long period and may promote genome instability and cell death. This review will focus on the poorly studied impact of neutron-gamma mixed beams with an emphasis on DNA damage and molecular mechanisms of repair. In case of BNCT, it is not clear which repair pathway is involved, and recent experimental work will be presented. Further understanding of BNCT-induced DDR mechanisms may lead to improved therapeutic efficiency against different tumors.

Keywords: BNCT (boron neutron capture therapy); DNA damage; DNA repair; complex DNA damage; high-LET; low-LET radiation; neutron mixed-beam.

Figure 1

(A) Types and effect of radiation according to linear energy transfer (LET): Low-LET radiation produces sparse ionization along its track, homogeneously within a cell. High-LET radiation causes dense ionization along its track. Mixed beam— both effects observed within a single cell (11, 12, 16, 17). (B) Radiation-induced DNA damage: DSBs induced by low-LET radiation are repaired by non-homologous end-joining pathway (NHEJ) alone or NHEJ and homologous recombination (HR). Mechanisms of repair of complex DSBs induced by high-LET radiation are not fully determined (9). Created with BioRender.com.

Figure 2

DNA-double-stranded breaks repair pathways: homologous recombination repair (HRR) and non-homologous end-joining (NHEJ) pathway induced by low and high linear energy transfer (LET) radiation (15, 23). Created with BioRender.com.