Molecular Signaling in Response to Charged Particle Exposures and its Importance in Particle Therapy

Abstract

Energetic, charged particles elicit an orchestrated DNA damage response (DDR) during their traversal through healthy tissues and tumors. Complex DNA damage formation, after exposure to high linear energy transfer (LET) charged particles, results in DNA repair foci formation, which begins within seconds. More protein modifications occur after high-LET, compared with low-LET, irradiation. Charged-particle exposure activates several transcription factors that are cytoprotective or cytodestructive, or that upregulate cytokine and chemokine expression, and are involved in bystander signaling. Molecular signaling for a survival or death decision in different tumor types and healthy tissues should be studied as prerequisite for shaping sensitizing and protective strategies. Long-term signaling and gene expression changes were found in various tissues of animals exposed to charged particles, and elucidation of their role in chronic and late effects of charged-particle therapy will help to develop effective preventive measures.

Keywords: DNA damage response; DNA repair foci; bystander effect; linear energy transfer; nuclear factor κB.

Figure 1.

Examples of complex DNA damage. For details, see text. Adapted from Georgakilas [113], DNA structure from Wikimedia Commons.

Figure 2.

Molecular signaling and outcome after charged particle exposure. For details, see text

Figure 3.

Formation of charged particle-induced foci at sites of complex DNA double strand breaks. For details, see text. Only proteins that were experimentally shown to accumulate at charged particle induced damage sites are shown. Adapted from Bekker-Jensen and Mailand [114] and references in the text. Not all proteins shown here might accumulate in every charged particle-induced focus; for example DNA-PK and Artemis are generally involved in nonhomologous end-joining, and BRCA1 and RPA in homologous recombination, indicating the branching into one of these DNA double-strand break repair pathways.