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.

Details

Title
Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro
Author
Matsuno, Yusuke 1 ; Atsumi, Yuko 2 ; Shimizu, Atsuhiro 2 ; Katayama, Kotoe 3   VIAFID ORCID Logo  ; Fujimori, Haruka 4 ; Hyodo, Mai 4 ; Minakawa, Yusuke 4 ; Nakatsu, Yoshimichi 5 ; Kaneko, Syuzo 6 ; Hamamoto, Ryuji 7 ; Shimamura, Teppei 8 ; Miyano, Satoru 3 ; Tsuzuki, Teruhisa 5 ; Hanaoka, Fumio 9 ; Yoshioka, Ken-ichi 2 

1  Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan; Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo, Japan 
2  Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan 
3  Human Genome Center, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan 
4  Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan; Biological Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan 
5  Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan 
6  Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan 
7  Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan; Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Chuo-ku, Tokyo, Japan 
8  Division of Systems Biology, Graduate School of Medicine, Nagoya University, Tsurumai-cho, Nagoya, Japan 
9  Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo, Japan; National Institute of Genetics, Mishima, Shizuoka, Japan 
Pages
1-13
Publication year
2019
Publication date
Sep 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-11760-2
ProQuest document ID
2283281861
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.