Whereas most endogenous and exogenous DNA damaging agents typically generate 
lesions that are relatively isolated and can be repaired easily, ionizing 
radiation (IR) also induces clustered lesions causing DNA double strand breaks 
(DSBs). Moreover, forms of IR characterized by high linear energy transfer (LET) 
induce not only isolated DSBs but also DSB clusters - multiple DSBs in close 
proximity -that pose increased risks for the cell. DSB clusters can destabilize 
chromatin locally and compromise processing of individual DSBs within the 
cluster. Since the discovery of chromothripsis, a phenomenon whereby multiple 
DSBs locally generated by a catastrophic event causes genomic rearrangements 
that feed carcinogenesis, DSB clusters receive increased attention also in the 
field of cancer. While formation of DSB clusters after exposure to high LET is a 
direct and inherent consequence of the spatial distribution of the constituting 
energy deposition events, also called track structure, the sources of local 
genomic shattering underpinning chromothripsis are under investigation. Notably, 
many consequences of DSB clusters in the affected genome reflect processing by 
pathways that have evolved to repair DSBs, but which operate with widely 
different degrees of fidelity. The molecular underpinnings and the basis of the 
underlying repair pathway choices that ultimately lead to the observed 
consequences from DSB clusters remain unknown. We developed a tractable model of 
DSB clustering that allows direct analysis in cells of the consequences of 
certain configurations of DSB clusters. We outline the rationale for the 
development of this model and describe its key characteristics. We summarize 
results suggesting that DSB clusters compromise the first-line DSB-processing 
pathways of c-NHEJ and HRR, increasing as a consequence the contribution of 
alt-EJ, which has high propensity of generating chromosomal rearrangements. The 
results suggest a mechanism for the increased toxicity of high LET radiation and 
the extensive genomic rearrangements associated with chromothripsis.