DNA-PKcs activates the Chk2-Brca1 pathway during mitosis to ensure chromosomal stability

Z. Shang, L. Yu, Y. F. Lin, S. Matsunaga, C. Y. Shen, B. P C Chen

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is known to have a critical role in DNA double-strand break repair. We have previously reported that DNA-PKcs is activated when cells enter mitosis and functions in mitotic spindle assembly and chromosome segregation. Here we report that DNA-PKcs is the upstream regulator of the Chk2-Brca1 pathway, which impacts microtubule dynamics, kinetochore attachment and chromosomal segregation in mitosis. Downstream from Chk2, Brca1 promotes monoubiquitination of γ-tubulin to inhibit microtubule nucleation and growth. We found that DNA-PKcs is essential for mitotic Chk2 phosphorylation at Thr68. As in Chk2- and Brca1-deficient cells, loss of DNA-PKcs resulted in chromosome misalignment and lagging during anaphase owing to elevation in microtubule dynamics. Importantly, these mitotic aberrations in DNA-PKcs-defective cells were alleviated by the overexpression of phosphomimetic Chk2 or Brca1 mutant proteins but not their wild-type counterparts. Taken together, these results demonstrate that DNA-PKcs regulates mitotic spindle organization and chromosomal instability via the Chk2-Brca1 signaling pathway.

Original languageEnglish (US)
Article number201349
JournalOncogenesis
Volume3
DOIs
StatePublished - Feb 18 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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