Abstract
Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.
Highlights
We have previously demonstrated that the inhibition of classical non-homologous end-joining (c-NHEJ) by highLET ionizing radiation (IR) results in a shift to PARP-1-dependent Alternative end-joining (alt-EJ) that is characterized by increased formation of structural chromosomal abnormalities (SCAs) [36]
IR modalities of different LET elicit distinct biological effects reflecting changes in double-strand breaks (DSBs) character and processing. What causes these changes? High-LET IR induces highly complex, as well as clustered DSBs that compromise the prevailing hierarchy in DSB repair programs and generate a shift from resection-independent c-NHEJ towards resection-dependent repair mechanisms. This is a clear adaptation cells make to necessities generated by the type of DSBs induced, and which dictate their processing [70]
It manifests with the engagement of lower fidelity repair pathways, presumably because of their lower overall operational requirements for chromatin stability, and their ability to deal with DNA
Summary
In the case of X-rays or γ-rays, there is a small build-up in absorbed dose at low depths followed by an exponential decline with increasing depth (Figure 2) This form of energy deposition is obviously suboptimal for treating deep-seated tumors [23,24]. In addition to the beneficial energy deposition characteristics of charged particles, HI, an additional advantage is that they can be magnetically focused and that they show reduced lateral scattering In this way, different field forms and sizes can be generated for an optimal tumor treatment. Enhanced ionization clustering generated by high-LET particles, as compared to secondary electrons produced by low-LET X-rays, correlates with increased complexity/clustering of the damage induced in the DNA (Figure 1). The data uncover that high-LET radiation beams generate highly complex γ-H2AX/53BP1 foci clusters with a larger overall size, increased irregularity and delayed resolution compared to low-LET γ-rays.
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