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Cell Cycle. 2013 Nov 15;12(22):3500-11. doi: 10.4161/cc.26459. Epub 2013 Sep 19.

microRNA-34a promotes DNA damage and mitotic catastrophe.

Author information

1
Department of Microbiology, Immunology and Cancer Biology; University of Virginia; Charlottesville, VA USA; Aging-Cancer Interface Group; LDS Medical Center; St. Petersburg, Russia.

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 G 2/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.

KEYWORDS:

53BP1; DNA damage; brain tumors; microRNA-34a; mitosis; mitotic catastrophe

PMID:
24091633
PMCID:
PMC3906336
DOI:
10.4161/cc.26459
[Indexed for MEDLINE]
Free PMC Article

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