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MicroRNA-145 Impairs Classical Non-Homologous End-Joining in Response to Ionizing Radiation-Induced DNA Double-Strand Breaks via Targeting DNA-PKcs.
- Source :
- Cells (2073-4409); May2022, Vol. 11 Issue 9, pN.PAG-N.PAG, 19p
- Publication Year :
- 2022
-
Abstract
- 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-PK<subscript>cs</subscript>) is a critical factor in this pathway; however, regulation of DNA-PK<subscript>cs</subscript> expression remains unknown. In this study, we demonstrate that miR-145 directly suppresses DNA-PK<subscript>cs</subscript> 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-PK<subscript>cs</subscript>. In addition, we show that the levels of Akt1 phosphorylation in cancer cells are correlated with miR-145 suppression and DNA-PK<subscript>cs</subscript> upregulation. Furthermore, the overexpression of miR-145 in Akt1-suppressed cells inhibited c-NHEJ by downregulating DNA-PK<subscript>cs</subscript>. These results reveal a novel miRNA-mediated regulation of DNA repair and identify miR-145 as an important regulator of c-NHEJ. [ABSTRACT FROM AUTHOR]
- Subjects :
- DOUBLE-strand DNA breaks
DNA repair
DNA damage
MICRORNA
CHROMOSOME abnormalities
Subjects
Details
- Language :
- English
- ISSN :
- 20734409
- Volume :
- 11
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- Cells (2073-4409)
- Publication Type :
- Academic Journal
- Accession number :
- 156848919
- Full Text :
- https://doi.org/10.3390/cells11091509