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miR-18a impairs DNA damage response through downregulation of ataxia telangiectasia mutated (ATM) kinase.
- Source :
-
PloS one [PLoS One] 2011; Vol. 6 (9), pp. e25454. Date of Electronic Publication: 2011 Sep 27. - Publication Year :
- 2011
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Abstract
- The DNA damage response (DDR) encompasses multi-step processes by which cells evolve to sense DNA damage, transduce the signal and initiate the repair of damaged DNA. Ataxia Telangiectasia Mutated (ATM) Kinase, which functions as the primary sensor and transducer of DNA damage signal, has been demonstrated to play an important role in the DDR and cancer prevention. Hence, understanding the molecular mechanisms underlying the regulation of ATM has received much attention. Here, we found that miR-18a was upregulated in both cell lines and patients' tissue samples of breast cancer. Furthermore, we demonstrated that ectopically expressing miR-18a downregulated ATM expression by directly targeting the ATM-3'-UTR and abrogated the IR-induced cell cycle arrest. Similar to the effect of ATM siRNA, overexpressing miR-18a in breast cancer cells reduced the DNA damage repair ability and the efficiency of homologous recombination-based DNA repair (HRR) and sensitized cells to γ-irradiation (IR) treatment. However, inhibition of miR-18a led to augmentation of DNA damage repair, increase of HRR efficiency and reduced cellular radiosensitivity. Moreover, we showed that the phorsphorylation level and nuclear foci formation of H2AX and 53BP1, the downstream substrates of ATM kinase, were significantly deceased in miR-18a overexpressing cells. Taken together, our results uncover a new regulatory mechanism of ATM expression and suggest that miR-18a might be a novel therapeutic target.
- Subjects :
- 3' Untranslated Regions genetics
Adult
Ataxia Telangiectasia Mutated Proteins
Breast Neoplasms genetics
Breast Neoplasms pathology
Cell Cycle Checkpoints genetics
Cell Cycle Proteins metabolism
Cell Line, Tumor
DNA-Binding Proteins metabolism
Female
Humans
Protein Serine-Threonine Kinases metabolism
Radiation Tolerance genetics
Recombinational DNA Repair genetics
Signal Transduction genetics
Tumor Suppressor Proteins metabolism
Cell Cycle Proteins genetics
DNA Damage genetics
DNA-Binding Proteins genetics
Down-Regulation genetics
MicroRNAs genetics
Protein Serine-Threonine Kinases genetics
Tumor Suppressor Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 6
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 21980462
- Full Text :
- https://doi.org/10.1371/journal.pone.0025454