Cellular premature senescence as a sublethal response to particle radiation: mechanistical challenges for multiscale modelling

Stress-induced premature senescence (SIPS) is one possible response to sub-lethal stimuli such as ionizing radiation-induced damage. Cells undergoing SIPS enter a state of quiescence; hence, they phenotypically resemble those entering the permanent growth arrest caused by physiological senescence, the ultimate fate encountered by normally dividing cells. However, despite a degree of overlap between the molecular pathways underlying physiological and premature senescence, there are substantial differences between the two phenomena, the most relevant of which regards the initiating event(s): whereas physiologically senescing cells stop dividing when their telomere sequences have shortened below a critical length, the mechanisms triggering the SIPS response are unclear. The activation of p53-controlled pathways, as well as of other gene products known to be involved in the DNA damage response (DDR) machinery point to a role for DNA lesions such as DNA DSBs, although it is also thought that SIPS may be brought about as a result of “generalized” cytogenetic damage. Because of the peculiar pattern by which energy deposition events are distributed along and around particle tracks (e.g. highly-localized damaging ionization clusters), ion beams can serve as a probe to shed light on the molecular scale at which SIPS may be triggered. Moreover, charged particles appear to be more effective at causing SIPS compared to photons. Traditionally, the higher effectiveness for a variety of radiobiological endpoints of charged particles vs. photons has been attributed to the higher linear energy transfer (LET) of the former type of radiation. Preliminary data will be presented that show qualitative and quantitative differences in the onset and time course of SIPS induced by different ion species at similar LET values. These results pose questions as to what lesions are relevant to SIPS, as to whether and how such lesion(s) may depend on the radiation quality and, finally, as to what modelling approach may best mechanistically link the initiating events with the sub-lethal senescence phenotype.