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Splicing function of mitotic regulators links R-loop-mediated DNA damage to tumor cell killing.

Authors
  • Wan, Yihan
  • Zheng, Xiaobin
  • Chen, Haiyang
  • Guo, Yuxuan
  • Jiang, Hao
  • He, Xiaonan
  • Zhu, Xueliang
  • Zheng, Yixian
Type
Published Article
Journal
Journal of Cell Biology
Publisher
Rockefeller University Press
Publication Date
Apr 27, 2015
Volume
209
Issue
2
Pages
235–246
Identifiers
DOI: 10.1083/jcb.201409073
PMID: 25918225
Source
Medline
License
Unknown

Abstract

Although studies suggest that perturbing mitotic progression leads to DNA damage and p53 activation, which in turn lead to either cell apoptosis or senescence, it remains unclear how mitotic defects trigger p53 activation. We show that BuGZ and Bub3, which are two mitotic regulators localized in the interphase nucleus, interact with the splicing machinery and are required for pre-mRNA splicing. Similar to inhibition of RNA splicing by pladienolide B, depletion of either BuGZ or Bub3 led to increased formation of RNA-DNA hybrids (R-loops), which led to DNA damage and p53 activation in both human tumor cells and primary cells. Thus, R-loop-mediated DNA damage and p53 activation offer a mechanistic explanation for apoptosis of cancer cells and senescence of primary cells upon disruption of the dual-function mitotic regulators. This demonstrates the importance of understanding the full range of functions of mitotic regulators to develop antitumor drugs.

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