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Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation
Dan Yan1, Wooi Loon Ng, Xiangming Zhang
1Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia, United States of America.
Background:
Radiotherapy kills tumor-cells by inducing DNA double strand breaks (DSBs). However, the efficient repair of tumors frequently prevents successful treatment. Therefore, identifying new practical sensitizers is an essential step towards successful radiotherapy. In this study, we tested the new hypothesis: identifying the miRNAs to target DNA DSB repair genes could be a new way for sensitizing tumors to ionizing radiation.
Principal Findings:
HERE, WE CHOSE TWO GENES: DNA-PKcs (an essential factor for non-homologous end-joining repair) and ATM (an important checkpoint regulator for promoting homologous recombination repair) as the targets to search their regulating miRNAs. By combining the database search and the bench work, we picked out miR-101. We identified that miR-101 could efficiently target DNA-PKcs and ATM via binding to the 3'- UTR of DNA-PKcs or ATM mRNA. Up-regulating miR-101 efficiently reduced the protein levels of DNA-PKcs and ATM in these tumor cells and most importantly, sensitized the tumor cells to radiation in vitro and in vivo.
Conclusions:
These data demonstrate for the first time that miRNAs could be used to target DNA repair genes and thus sensitize tumors to radiation. These results provide a new way for improving tumor radiotherapy.
Insights
Researchers identified microRNAs (miRNAs) targeting DNA repair genes as a novel strategy to enhance radiotherapy effectiveness. Upregulating miR-101 sensitized tumor cells to radiation by reducing DNA repair proteins, offering a new approach for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Radiotherapy combats cancer by inducing DNA double-strand breaks (DSBs), but tumor repair mechanisms often limit treatment efficacy.
- Developing effective radiosensitizers is crucial for improving cancer treatment outcomes.
- This study investigates targeting DNA DSB repair genes with microRNAs (miRNAs) as a novel radiosensitization strategy.
Purpose of the Study:
- To explore the potential of miRNAs in targeting DNA double-strand break repair genes for radiosensitization.
- To identify specific miRNAs that can modulate key DNA repair pathways in tumor cells.
Main Methods:
- Utilized database searches and experimental validation to identify miRNAs targeting DNA-PKcs and ATM, key DNA repair and checkpoint genes.
- Investigated the binding of identified miRNAs to the 3'-untranslated region (UTR) of target mRNAs.
- Assessed the effect of miRNA upregulation on protein levels of DNA repair factors and tumor cell radiosensitivity in vitro and in vivo.
Main Results:
- miR-101 was identified as a miRNA that directly targets both DNA-PKcs and ATM by binding to their 3'-UTRs.
- Upregulation of miR-101 led to decreased protein expression of DNA-PKcs and ATM in tumor cells.
- Enhanced miR-101 levels significantly sensitized tumor cells to ionizing radiation, both in vitro and in vivo.
Conclusions:
- Demonstrates for the first time that miRNAs can effectively target DNA repair genes to enhance tumor radiosensitivity.
- Presents a novel therapeutic strategy utilizing miRNAs for improving the efficacy of radiotherapy in cancer treatment.
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