Abstract
Efficient and error-free DNA repair is critical for safeguarding genome integrity, yet it is also linked to radio-and chemoresistance of malignant tumors. miR-34a, a potent tumor suppressor, influences a large set of p53-regulated genes and contributes to p53-mediated apoptosis. However, the effects of miR-34a on the processes of DNA damage and repair are not entirely understood. We explored tet-inducible miR-34a-expressing human p53 wild-type and R273H p53 mutant GBM cell lines, and found that miR-34a influences the broad spectrum of 53BP1-mediated DNA damage response. It escalates both post-irradiation and endogenous DNA damage, abrogates radiation-induced G2/M arrest and drastically increases the number of irradiated cells undergoing mitotic catastrophe. Furthermore, miR-34a downregulates 53BP1 and inhibits its recruitment to the sites of DNA double-strand breaks. We conclude that whereas miR-34a counteracts DNA repair, it also contributes to the p53-independent elimination of distressed cells, thus preventing the rise of genomic instability in tumor cell populations. These properties of miR-34a can potentially be exploited for DNA damage-effecting therapies of malignancies.
Original language | English |
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Pages (from-to) | 3500-3511 |
Number of pages | 12 |
Journal | Cell Cycle |
Volume | 12 |
Issue number | 22 |
DOIs | |
State | Published - Nov 15 2013 |
Keywords
- 53BP1
- Brain tumors
- DNA damage
- MicroRNA-34a
- Mitosis
- Mitotic catastrophe