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DNA single-strand break-induced DNA damage response causes heart failure

Author

Listed:
  • Tomoaki Higo

    (Osaka University Graduate School of Medicine)

  • Atsuhiko T. Naito

    (Osaka University Graduate School of Medicine
    CREST
    The University of Tokyo Graduate School of Medicine
    Present address: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Tokyo 143-8540, Japan)

  • Tomokazu Sumida

    (CREST
    The University of Tokyo Graduate School of Medicine)

  • Masato Shibamoto

    (Osaka University Graduate School of Medicine)

  • Katsuki Okada

    (Osaka University Graduate School of Medicine)

  • Seitaro Nomura

    (CREST
    The University of Tokyo Graduate School of Medicine)

  • Akito Nakagawa

    (Osaka University Graduate School of Medicine)

  • Toshihiro Yamaguchi

    (The University of Tokyo Graduate School of Medicine)

  • Taku Sakai

    (Osaka University Graduate School of Medicine)

  • Akihito Hashimoto

    (Osaka University Graduate School of Medicine)

  • Yuki Kuramoto

    (Osaka University Graduate School of Medicine)

  • Masamichi Ito

    (The University of Tokyo Graduate School of Medicine)

  • Shungo Hikoso

    (Osaka University Graduate School of Medicine)

  • Hiroshi Akazawa

    (Osaka University Graduate School of Medicine
    CREST
    The University of Tokyo Graduate School of Medicine)

  • Jong-Kook Lee

    (Osaka University Graduate School of Medicine
    CREST)

  • Ichiro Shiojima

    (CREST
    Kansai Medical University)

  • Peter J. McKinnon

    (ST. Jude Children’s Research Hospital)

  • Yasushi Sakata

    (Osaka University Graduate School of Medicine)

  • Issei Komuro

    (CREST
    The University of Tokyo Graduate School of Medicine
    Institute for Academic Initiatives, Osaka University)

Abstract

The DNA damage response (DDR) plays a pivotal role in maintaining genome integrity. DNA damage and DDR activation are observed in the failing heart, however, the type of DNA damage and its role in the pathogenesis of heart failure remain elusive. Here we show the critical role of DNA single-strand break (SSB) in the pathogenesis of pressure overload-induced heart failure. Accumulation of unrepaired SSB is observed in cardiomyocytes of the failing heart. Unrepaired SSB activates DDR and increases the expression of inflammatory cytokines through NF-κB signalling. Pressure overload-induced heart failure is more severe in the mice lacking XRCC1, an essential protein for SSB repair, which is rescued by blocking DDR activation through genetic deletion of ATM, suggesting the causative role of SSB accumulation and DDR activation in the pathogenesis of heart failure. Prevention of SSB accumulation or persistent DDR activation may become a new therapeutic strategy against heart failure.

Suggested Citation

  • Tomoaki Higo & Atsuhiko T. Naito & Tomokazu Sumida & Masato Shibamoto & Katsuki Okada & Seitaro Nomura & Akito Nakagawa & Toshihiro Yamaguchi & Taku Sakai & Akihito Hashimoto & Yuki Kuramoto & Masamic, 2017. "DNA single-strand break-induced DNA damage response causes heart failure," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15104
    DOI: 10.1038/ncomms15104
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    Cited by:

    1. Toshiyuki Ko & Seitaro Nomura & Shintaro Yamada & Kanna Fujita & Takanori Fujita & Masahiro Satoh & Chio Oka & Manami Katoh & Masamichi Ito & Mikako Katagiri & Tatsuro Sassa & Bo Zhang & Satoshi Hatsu, 2022. "Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Haichao Zhao & Jia Li & Zhongsheng You & Howard D. Lindsay & Shan Yan, 2024. "Distinct regulation of ATM signaling by DNA single-strand breaks and APE1," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Megha Jhanji & Chintada Nageswara Rao & Jacob C. Massey & Marion C. Hope & Xueyan Zhou & C. Dirk Keene & Tao Ma & Michael D. Wyatt & Jason A. Stewart & Mathew Sajish, 2022. "Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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