Loss of Hus1 sensitizes cells to etoposide-induced apoptosis by regulating BH3-only proteins

C. L. Meyerkord, Yoshinori Takahashi, R. Araya, N. Takada, R. S. Weiss, Hong-Gang Wang

Research output: Contribution to journalArticle

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Abstract

The Rad9-Rad1-Hus1 (9-1-1) cell cycle checkpoint complex plays a key role in the DNA damage response. Cells with a defective 9-1-1 complex have been shown to be sensitive to apoptosis induced by certain types of genotoxic stress. However, the mechanism linking the loss of a functional 9-1-1 complex to the cell death machinery has yet to be determined. Here, we report that etoposide treatment dramatically upregulates the BH3-only proteins, Bim and Puma, in Hus1-deficient cells. Inhibition of either Bim or Puma expression in Hus1-knockout cells confers significant resistance to etoposide-induced apoptosis, whereas knockdown of both proteins results in further resistance, suggesting that Bim and Puma cooperate in sensitizing Hus1-deficient cells to etoposide treatment. Moreover, we found that Rad9 collaborates with Bim and Puma to sensitize Hus1-deficient cells to etoposide-induced apoptosis. In response to DNA damage, Rad9 localizes to chromatin in Hus1-wild-type cells, whereas in Hus1-deficient cells, it is predominantly located in the cytoplasm where it binds to Bcl-2. Taken together, these results suggest that loss of Hus1 sensitizes cells to etoposide-induced apoptosis not only by inducing Bim and Puma expressions but also by releasing Rad9 into the cytosol to augment mitochondrial apoptosis.

Original languageEnglish (US)
Pages (from-to)7248-7259
Number of pages12
JournalOncogene
Volume27
Issue number58
DOIs
StatePublished - Dec 11 2008

Fingerprint

Etoposide
Puma
Apoptosis
Proteins
DNA Damage
Cell Cycle Checkpoints
Cytosol
Chromatin
Cytoplasm
Cell Death
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Meyerkord, C. L. ; Takahashi, Yoshinori ; Araya, R. ; Takada, N. ; Weiss, R. S. ; Wang, Hong-Gang. / Loss of Hus1 sensitizes cells to etoposide-induced apoptosis by regulating BH3-only proteins. In: Oncogene. 2008 ; Vol. 27, No. 58. pp. 7248-7259.
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Loss of Hus1 sensitizes cells to etoposide-induced apoptosis by regulating BH3-only proteins. / Meyerkord, C. L.; Takahashi, Yoshinori; Araya, R.; Takada, N.; Weiss, R. S.; Wang, Hong-Gang.

In: Oncogene, Vol. 27, No. 58, 11.12.2008, p. 7248-7259.

Research output: Contribution to journalArticle

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