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

Yusuke Matsuno, Yuko Atsumi, Atsuhiro Shimizu, Kotoe Katayama, Haruka Fujimori, Mai Hyodo, Yusuke Minakawa, Yoshimichi Nakatsu, Syuzo Kaneko, Ryuji Hamamoto, Teppei Shimamura, Satoru Miyano, Teruhisa Tsuzuki, Fumio Hanaoka and Ken-ichi Yoshioka ()
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Yusuke Matsuno: National Cancer Center Research Institute, Tsukiji
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
Mai Hyodo: National Cancer Center Research Institute, Tsukiji
Yusuke Minakawa: National Cancer Center Research Institute, Tsukiji
Yoshimichi Nakatsu: Kyushu University, Maidashi
Syuzo Kaneko: National Cancer Center Research Institute, Tsukiji
Ryuji Hamamoto: National Cancer Center Research Institute, Tsukiji
Teppei Shimamura: Nagoya University, Tsurumai-cho
Satoru Miyano: University of Tokyo, Shirokanedai
Teruhisa Tsuzuki: Kyushu University, Maidashi
Fumio Hanaoka: Gakushuin University, Mejiro
Ken-ichi Yoshioka: National Cancer Center Research Institute, Tsukiji

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11760-2

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