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.
|Number of pages||12|
|State||Published - Nov 15 2013|
Bibliographical noteFunding Information:
We thank Jan A Redick, Stacey Guillot, Barbee Herrmann, Stephen Turner, Joanne Lannigan, Michael Solga, Benjamin J Purow, Benjamin Kefas, and Anatolii Ryndin for assistance in various aspects during preparation of this manuscript. This work was supported by NIH grants RO1 NS045209 and RO1 CA134843A (R Abounader).
- Brain tumors
- DNA damage
- Mitotic catastrophe
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology
- Cell Biology