MicroRNA-34a promotes DNA damage and mitotic catastrophe

Alexander V. Kofman, Jungeun Kim, So Yeon Park, Evan Dupart, Christopher Letson, Yongde Bao, Kai Ding, Quan Chen, David Schiff, James Larner, Roger Abounader

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)3500-3511
Number of pages12
JournalCell Cycle
Volume12
Issue number22
DOIs
StatePublished - Nov 15 2013
Externally publishedYes

Keywords

  • 53BP1
  • Brain tumors
  • DNA damage
  • MicroRNA-34a
  • Mitosis
  • Mitotic catastrophe

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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