期刊
CELLS
卷 11, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/cells11091509
关键词
classical non-homologous end-joining pathway (c-NHEJ); DSBs; DNA-PKcs; microRNA
类别
资金
- National Research Foundation of Korea (NRF) - Ministry of Science, ICT, and Future Planning [NRF-2015R1A5A2009070, NRF-2020R1A2C2003423]
This study demonstrates that miR-145 suppresses DNA-PKcs expression, affecting DNA double-strand break repair and rendering cells sensitive to ionizing radiation. Additionally, miR-145 inhibition is associated with increased Akt1 phosphorylation and upregulation of DNA-PKcs in cancer cells.
DNA double-strand breaks (DSBs) are one of the most lethal types of DNA damage due to the fact that unrepaired or mis-repaired DSBs lead to genomic instability or chromosomal aberrations, thereby causing cell death or tumorigenesis. The classical non-homologous end-joining pathway (c-NHEJ) is the major repair mechanism for rejoining DSBs, and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is a critical factor in this pathway; however, regulation of DNA-PKcs expression remains unknown. In this study, we demonstrate that miR-145 directly suppresses DNA-PKcs by binding to the 3 '-UTR and inhibiting translation, thereby causing an accumulation of DNA damage, impairing c-NHEJ, and rendering cells hypersensitive to ionizing radiation (IR). Of note, miR-145-mediated suppression of DNA damage repair and enhanced IR sensitivity were both reversed by either inhibiting miR-145 or overexpressing DNA-PKcs. In addition, we show that the levels of Akt1 phosphorylation in cancer cells are correlated with miR-145 suppression and DNA-PKcs upregulation. Furthermore, the overexpression of miR-145 in Akt1-suppressed cells inhibited c-NHEJ by downregulating DNA-PKcs. These results reveal a novel miRNA-mediated regulation of DNA repair and identify miR-145 as an important regulator of c-NHEJ.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据