Links between DNA polymerase beta expression and sensitivity to bleomycin.


Bleomycin (BLM), an important anti-tumor antibiotic, enables cell ...
Bleomycin (BLM), an important anti-tumor antibiotic, enables cell death through oxidative DNA damage mediated by reactive oxygen species (ROS). However, increasing cellular resistance has become a serious limitation to its clinical application. Base excision repair (BER), the major pathway for repairing oxidative bases, is involved in resistance of DNA-damaging anticancer drugs. DNA polymerase beta (pol beta), a critical BER enzyme, has been reported to play a crucial role in combating BLM-induced oxidative DNA damage, as a result, pol beta inhibition may increase the sensitivity to BLM. To test this hypothesis, we evaluated the sensitivity to BLM using mouse embryo fibroblasts (MEFs) with distinct pol beta expression levels (wild-type, pol beta deficiency) and explored the underlying mechanisms. The results showed that cell viability of pol beta-deficient MEFs was significantly lower than that of isogenic wild type when treated with the same BLM dosage. In addition, increased ROS level, DNA single strand breaks, and chromosomal breakage were observed in pol beta deficient cells, indicating impaired DNA repair and enhanced oxidative DNA damage under pol beta deficiency. In agreement with the findings, an enhanced hprt gene mutation frequency was also detected in pol beta null cells. In summary, this study demonstrated that BLM-induced DNA damage could be repaired through BER pathway and absence of pol beta allows oxidative DNA/chromosome damage and gene mutation, which contributes to BLM hypersensitivity.



Nucleotide Analogs / Template Lesions, Fidelity


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