Abstract
Ionizing radiation generates a broad spectrum of oxidative DNA lesions, including oxidized base products, abasic sites, single-strand breaks and double-strand breaks. The CUX1 protein was recently shown to function as an auxiliary factor that stimulates enzymatic activities of OGG1 through its CUT domains. In the present study, we investigated the requirement for CUX1 and OGG1 in the resistance to radiation. Cancer cell survival following ionizing radiation is reduced by CUX1 knockdown and increased by higher CUX1 expression. However, CUX1 knockdown is sufficient by itself to reduce viability in many cancer cell lines that exhibit high levels of reactive oxygen species (ROS). Consequently, clonogenic results expressed relative to that of non-irradiated cells indicate that CUX1 knockdown confers no or modest radiosensitivity to cancer cells with high ROS. A recombinant protein containing only two CUT domains is sufficient for rapid recruitment to DNA damage, acceleration of DNA repair and increased survival following radiation. In agreement with these findings, OGG1 knockdown and treatment of cells with OGG1 inhibitors sensitize cancer cells to radiation. Together, these results validate CUX1 and more specifically the CUT domains as therapeutic targets.
Highlights
Half of all cancer patients receive ionizing radiation as a part of treatment
The results show that Cut homeobox 1 (CUX1) knockdown does not affect radiosensitivity in DLD-1, T98G and HCC827 cells, while it has a modest effect in MDA-MB-231, HT29, U251 and A549 cells (Figure 1C)
CUX1 knockdown did not decrease reactive oxygen species (ROS) levels (Figure 1D). These results suggest that the same mechanism, an excess of oxidative DNA damage, explains the decrease in clonogenic efficiency observed in these cell lines following CUX1 knockdown
Summary
Half of all cancer patients receive ionizing radiation as a part of treatment. Analysis of radiation-induced DNA damage using lesion-specific enzymes and pulse-field gel electrophoresis established that double-strand breaks represent only about 20% of clustered damage sites, with the remaining 80% being non-DSB clusters ([8,9,10,11], reviewed in [12, 13]). There is much evidence to show that clustered DNA lesions www.impactjournals.com/oncotarget are more difficult to repair and persist longer [16,17,18,19,20], reviewed in [12, 13] This is in stark contrast to the efficient repair of isolated DNA lesions produced by endogenous reactive oxygen species [21]. In addition to radiationinduced cytotoxicity resulting from DSBs and non-DSB clusters, replicating blocking lesions such as thymine glycol, 4, 6-diamino-5-formamidopyrimidine (FapyA) and 2, 6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), are toxic and can be lethal if not rapidly repaired [24,25,26,27]
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