Abstract
The catalytic subunit of DNA‐dependent protein kinase (DNA‐PKcs) is known to play a critical role in DNA double‐strand break repair. We 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 due to elevation in microtubule dynamics. Importantly, these mitotic aberrations in DNA‐PKcs‐defective cells were alleviated by over‐expression 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.Grant Funding Source: NIH, CA166677
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