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Bach1 inhibits oxidative stress–induced cellular senescence by impeding p53 function on chromatin

Nature Structural & Molecular Biology volume 15, pages 12461254 (2008) | Download Citation

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Abstract

Cellular senescence is one of the key strategies to suppress expansion of cells with mutations. Senescence is induced in response to genotoxic and oxidative stress. Here we show that the transcription factor Bach1 (BTB and CNC homology 1, basic leucine zipper transcription factor 1), which inhibits oxidative stress-inducible genes, is a crucial negative regulator of oxidative stress–induced cellular senescence. Bach1-deficient murine embryonic fibroblasts showed a propensity to undergo more rapid and profound p53-dependent premature senescence than control wild-type cells in response to oxidative stress. Bach1 formed a complex that contained p53, histone deacetylase 1 and nuclear co-repressor N-coR. Bach1 was recruited to a subset of p53 target genes and contributed to impeding p53 action by promoting histone deacetylation. Because Bach1 is regulated by oxidative stress and heme, our data show that Bach1 connects oxygen metabolism and cellular senescence as a negative regulator of p53.

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Acknowledgements

We thank T. Jacks (Massachusetts Institute of Technology), T.P. Yao (Duke University), K. Tanimoto (Hiroshima University), H. Ogawa (National Institute of Basic Biology), N. Tanaka (Nippon Medical School) and K. Umesono for providing plasmids and antibodies; Y. Ishikawa and K. Nakayama (Tohoku University) for providing p53−/− MEFs; and M. Katsuki (National Institute of Basic Biology) for providing Trp53−/− mice. We also thank M. Kobayashi and Y. Taya for comments on the manuscript; S. Tashiro and T. Ide for valuable advice to initiate the project; M. Ikura for help in cell culturing; and M. Yoshizumi and N. Tanaka for advice. This work was supported by Grants-in-aid and the Network Medicine Global-COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants from the Uehara Foundation, the Takeda Foundation and the Astellas Foundation for Research on Metabolic Disorders.

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Author notes

    • Yoshihiro Dohi

    Present address: Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8551, Japan.

Affiliations

  1. Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai 980-8575, Japan.

    • Yoshihiro Dohi
    • , Tsuyoshi Ikura
    • , Yasutake Katoh
    • , Kazushige Ota
    • , Ayako Nakanome
    • , Akihiko Muto
    •  & Kazuhiko Igarashi
  2. Department of Cardiovascular Physiology and Medicine, Hiroshima University Graduate School of Biomedical Science, Kasumi 1-2-3, Hiroshima 734-8551, Japan.

    • Yoshihiro Dohi
    •  & Shinji Omura
  3. Japanese Foundation for Cancer Research, Cancer Institute, Ariake 3-10-6, Tokyo 135-8550, Japan.

    • Yutaka Hoshikawa
    •  & Tetsuo Noda
  4. Center for Medical Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji Chuo-ku, Tokyo 104-0045, Japan.

    • Tsutomu Ohta
  5. Chemical Genetics Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.

    • Akihiro Ito
    •  & Minoru Yoshida
  6. Japan Science and Technology Corporation (JST), CREST Research Project, Kawasaki, Saitama 332-0012, Japan.

    • Minoru Yoshida

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Contributions

Y.D., T.I., Y.K., K.O., A.N., A.M., S.O., A.I. and M.Y. contributed to performing and assisting with experiments; A.M. and T.O. contributed to performing gene expression profiling; Y.H. and T.N. contributed to performing MS/MS analysis; K.I. designed and conceptualized the study; Y.D., T.I., T.N. and K.I. interpreted the data and Y.D., T.I. and K.I. wrote the manuscript. All authors made comments on the manuscript.

Corresponding author

Correspondence to Kazuhiko Igarashi.

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DOI

https://doi.org/10.1038/nsmb.1516

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