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Regulation of histone modification and chromatin structure by the p53–PADI4 pathway

Author

Listed:
  • Chizu Tanikawa

    (Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo)

  • Martha Espinosa

    (Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo
    Center for Research and Advanced Studies)

  • Akari Suzuki

    (Laboratory for Rheumatic Diseases, Center for Genomic Medicine, RIKEN)

  • Ken Masuda

    (Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo)

  • Kazuhiko Yamamoto

    (Laboratory for Rheumatic Diseases, Center for Genomic Medicine, RIKEN
    Graduate School of Medicine, the University of Tokyo)

  • Eiju Tsuchiya

    (Saitama Cancer Center
    Kanagawa Cancer Center Research Institute)

  • Koji Ueda

    (Laboratory for Biomarker Development, Center for Genomic Medicine, RIKEN)

  • Yataro Daigo

    (Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo
    Shiga University of Medical Science)

  • Yusuke Nakamura

    (Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo)

  • Koichi Matsuda

    (Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo)

Abstract

Histone proteins are modified in response to various external signals; however, their mechanisms are still not fully understood. Citrullination is a post-transcriptional modification that converts arginine in proteins into citrulline. Here we show in vivo and in vitro citrullination of the arginine 3 residue of histone H4 (cit-H4R3) in response to DNA damage through the p53–PADI4 pathway. We also show DNA damage-induced citrullination of Lamin C. Cit-H4R3 and citrullinated Lamin C localize around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 leads to chromatin decondensation and promotes DNA cleavage, whereas Padi4−/− mice exhibit resistance to radiation-induced apoptosis in the thymus. Furthermore, the level of cit-H4R3 is negatively correlated with p53 protein expression and with tumour size in non-small cell lung cancer tissues. Our findings reveal that cit-H4R3 may be an 'apoptotic histone code' to detect damaged cells and induce nuclear fragmentation, which has a crucial role in carcinogenesis.

Suggested Citation

  • Chizu Tanikawa & Martha Espinosa & Akari Suzuki & Ken Masuda & Kazuhiko Yamamoto & Eiju Tsuchiya & Koji Ueda & Yataro Daigo & Yusuke Nakamura & Koichi Matsuda, 2012. "Regulation of histone modification and chromatin structure by the p53–PADI4 pathway," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1676
    DOI: 10.1038/ncomms1676
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