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

Nature Structural & Molecular Biology volume 15, pages 1246–1254 (2008)Cite this article

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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Figure 1: Bach1 deficiency resulted in reduced proliferation in MEFs.
Figure 2: Oxidative stress–induced premature senescence in Bach1−/− (KO) MEFs.
Figure 3: p53-dependent senescence in Bach1−/− MEFs.
Figure 4: Inhibition of Ras-induced cellular senescence in MEFs by Bach1.
Figure 5: Bach1 repressed a subset of p53 target genes.
Figure 6: Purification of the Bach1 complex.
Figure 7: Recruitment of Bach1 to p53 target genes.
Figure 8: Bach1 facilitates repression of target genes by recruiting Hdac1.

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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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  1. Yoshihiro Dohi

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

Authors and 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, 351-0198, Saitama, Japan

    Akihiro Ito & Minoru Yoshida

  6. Japan Science and Technology Corporation (JST), CREST Research Project, Kawasaki, 332-0012, Saitama, 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.

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Correspondence to Kazuhiko Igarashi.

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Dohi, Y., Ikura, T., Hoshikawa, Y. et al. Bach1 inhibits oxidative stress–induced cellular senescence by impeding p53 function on chromatin. Nat Struct Mol Biol 15, 1246–1254 (2008). https://doi.org/10.1038/nsmb.1516

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