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Clustered DNA Damage Leads to Complex Genetic Changes in Irradiated Human Cells¹

Medical Research Council, Radiation & Genome Stability Unit, Harwell, Oxfordshire OX11 0RD, England

Densely ionizing radiations interact with DNA to cause heavily clustered sites of damage that are difficult to repair correctly. We have been able to determine for the first time the breakpoints of several very large deletions induced by densely ionizing radiation in diploid human cells and show that damage clustering is reflected in the complexity of mutations. Intra- and interchromosomal insertions and inversions occur at the sites of some large deletions. Short sequence repeats are commonly found at the breakpoints, showing that microhomologies help patch damage sites. We suggest that novel fragments found in complex rearrangements derive from other sites of radiation damage in the same cell. These transmissible molecular changes are echoed by visible chromosome rearrangements many days after irradiation and are likely to contribute significantly to the carcinogenic properties of densely ionizing radiations.