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Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro

Author

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  • Yusuke Matsuno

    (National Cancer Center Research Institute, Tsukiji
    Tokyo University of Science, Kagurazaka)

  • Yuko Atsumi

    (National Cancer Center Research Institute, Tsukiji)

  • Atsuhiro Shimizu

    (National Cancer Center Research Institute, Tsukiji)

  • Kotoe Katayama

    (University of Tokyo, Shirokanedai)

  • Haruka Fujimori

    (National Cancer Center Research Institute, Tsukiji
    Tokyo University of Science, Niijuku)

  • Mai Hyodo

    (National Cancer Center Research Institute, Tsukiji
    Tokyo University of Science, Niijuku)

  • Yusuke Minakawa

    (National Cancer Center Research Institute, Tsukiji
    Tokyo University of Science, Niijuku)

  • Yoshimichi Nakatsu

    (Kyushu University, Maidashi)

  • Syuzo Kaneko

    (National Cancer Center Research Institute, Tsukiji)

  • Ryuji Hamamoto

    (National Cancer Center Research Institute, Tsukiji
    RIKEN Center for Advanced Intelligence Project, Chuo-ku)

  • Teppei Shimamura

    (Nagoya University, Tsurumai-cho)

  • Satoru Miyano

    (University of Tokyo, Shirokanedai)

  • Teruhisa Tsuzuki

    (Kyushu University, Maidashi)

  • Fumio Hanaoka

    (Gakushuin University, Mejiro
    National Institute of Genetics, Mishima)

  • Ken-ichi Yoshioka

    (National Cancer Center Research Institute, Tsukiji)

Abstract

Mismatch repair (MMR)-deficient cancers are characterized by microsatellite instability (MSI) and hypermutation. However, it remains unclear how MSI and hypermutation arise and contribute to cancer development. Here, we show that MSI and hypermutation are triggered by replication stress in an MMR-deficient background, enabling clonal expansion of cells harboring ARF/p53-module mutations and cells that are resistant to the anti-cancer drug camptothecin. While replication stress-associated DNA double-strand breaks (DSBs) caused chromosomal instability (CIN) in an MMR-proficient background, they induced MSI with concomitant suppression of CIN via a PARP-mediated repair pathway in an MMR-deficient background. This was associated with the induction of mutations, including cancer-driver mutations in the ARF/p53 module, via chromosomal deletions and base substitutions. Immortalization of MMR-deficient mouse embryonic fibroblasts (MEFs) in association with ARF/p53-module mutations was ~60-fold more efficient than that of wild-type MEFs. Thus, replication stress-triggered MSI and hypermutation efficiently lead to clonal expansion of cells with abrogated defense systems.

Suggested Citation

  • Yusuke Matsuno & Yuko Atsumi & Atsuhiro Shimizu & Kotoe Katayama & Haruka Fujimori & Mai Hyodo & Yusuke Minakawa & Yoshimichi Nakatsu & Syuzo Kaneko & Ryuji Hamamoto & Teppei Shimamura & Satoru Miyano, 2019. "Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11760-2
    DOI: 10.1038/s41467-019-11760-2
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    Cited by:

    1. Miho M. Suzuki & Kenta Iijima & Koichi Ogami & Keiko Shinjo & Yoshiteru Murofushi & Jingqi Xie & Xuebing Wang & Yotaro Kitano & Akira Mamiya & Yuji Kibe & Tatsunori Nishimura & Fumiharu Ohka & Ryuta S, 2023. "TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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