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.

Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair

“…The reaction produces high LET α -particles of enhanced damaging potential ideally solely on the desired target tumour area that is SOBP, without damaging neighbouring normal tissues (Refs 49, 50).…”

Physical bases of Boron Neutron Capture Therapy, Dosimetry, and Its Mechanisms of Action - Critical Overview of the Literature

“…Low-LET radiation ionizes sparsely, while high-LET radiation causes denser ionization along the track and can lead to more complex DNA damages. DNA damage after high-LET radiation remains unrepaired for a long time, leading to genome instability or death of the cell [44]. The density of radiation affects the presence and quality of the radiationinduced DSB.…”

“…The DNA-DSB repair process is complex and depends on many factors, including cell cycle phase and checkpoints, DSB-inducing agents, ncRNAs, and various gene mutations characterized by different cancer cell lines. Several attempts to investigate specific cellular DNA damage response induced by mixed neutron-gamma field has been taken over the last years [44,[47][48][49]. Despite that, this phenomenon is not fully understood and determined.…”

Physical Bases of Boron Neutron Capture Therapy, Dosimetry, and Its Mechanisms of Action—A Critical Overview of the Literature

“…Low-LET radiation ionizes sparsely, whereas high-LET radiation causes denser ionization along the track and can lead to more complex DNA damage. DNA damage after high-LET radiation remains unrepaired for a long time, leading to genome instability or cell death [37]. The density of radiation affects the presence and quality of radiation-induced DSB.…”

“…The DNA-DSB repair process is complex and depends on many factors, including cell cycle phase and checkpoints, DSB-inducing agents, ncRNAs, and various gene mutations characterized by different cancer cell lines. Several attempts have been made over the past few years to investigate the specific response to cellular DNA damage induced by a mixed neutron-gamma field [37,40,41]. Despite that, this phenomenon is not fully understood and determined.…”