Abstract
Cells manage to survive, thrive, and divide with high accuracy despite the constant threat of DNA damage. Cells have evolved with several systems that efficiently repair spontaneous, isolated DNA lesions with a high degree of accuracy. Ionizing radiation and a few radiomimetic chemicals can produce clustered DNA damage comprising complex arrangements of single-strand damage and DNA double-strand breaks (DSBs). There is substantial evidence that clustered DNA damage is more mutagenic and cytotoxic than isolated damage. Radiation-induced clustered DNA damage has proven difficult to study because the spectrum of induced lesions is very complex, and lesions are randomly distributed throughout the genome. Nonetheless, it is fairly well-established that radiation-induced clustered DNA damage, including non-DSB and DSB clustered lesions, are poorly repaired or fail to repair, accounting for the greater mutagenic and cytotoxic effects of clustered lesions compared to isolated lesions. High linear energy transfer (LET) charged particle radiation is more cytotoxic per unit dose than low LET radiation because high LET radiation produces more clustered DNA damage. Studies with I-SceI nuclease demonstrate that nuclease-induced DSB clusters are also cytotoxic, indicating that this cytotoxicity is independent of radiogenic lesions, including single-strand lesions and chemically “dirty” DSB ends. The poor repair of clustered DSBs at least in part reflects inhibition of canonical NHEJ by short DNA fragments. This shifts repair toward HR and perhaps alternative NHEJ, and can result in chromothripsis-mediated genome instability or cell death. These principals are important for cancer treatment by low and high LET radiation.
Highlights
Cells cope with a tremendous amount of spontaneous DNA damage that arises from naturally occurring reactive oxygen species (ROS), reactive nitrogen and carbonyl species, lipid peroxidation products, the chemical lability of DNA, and other mechanisms [1]
double-strand breaks (DSBs) are generated when closely opposed single-strand lesions are processed by base excision repair (BER) or nucleotide excision repair (NER), as these processes create intermediates with single-strand breaks (SSBs) or single-strand gaps [9,10,11,12]
We focus on DSB clusters, including their induction by radiation; biochemical and molecular genetic aspects of repair; the cellular consequences of mis-repair or failed repair; and their importance in cancer radiotherapy
Summary
Cells cope with a tremendous amount of spontaneous DNA damage that arises from naturally occurring reactive oxygen species (ROS), reactive nitrogen and carbonyl species, lipid peroxidation products, the chemical lability of DNA, and other mechanisms [1]. DSBs are generated when closely opposed single-strand lesions are processed by base excision repair (BER) or nucleotide excision repair (NER), as these processes create intermediates with SSBs or single-strand gaps [9,10,11,12] Both isolated and clustered DSBs are induced by ionizing radiation [13]. DSB clusters, induced by ionizing radiation, are especially challenging to repair, and are more cytotoxic, mutagenic, and genome destabilizing than isolated DSBs. The picture that emerges is that repair efficiency and accuracy decrease, and mutation and cytotoxicity increase as the complexity of DNA damage increases from isolated single-strand lesions to clustered double-strand lesions (Figure 1). For further information about clustered DNA lesions from the perspectives of radiation physics modeling, chemistry, detection, biology, and genetic consequences, the reader is directed to the following seminal reports and excellent reviews: [13,23,25,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]
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