TY - JOUR
T1 - Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro
AU - Matsuno, Yusuke
AU - Atsumi, Yuko
AU - Shimizu, Atsuhiro
AU - Katayama, Kotoe
AU - Fujimori, Haruka
AU - Hyodo, Mai
AU - Minakawa, Yusuke
AU - Nakatsu, Yoshimichi
AU - Kaneko, Syuzo
AU - Hamamoto, Ryuji
AU - Shimamura, Teppei
AU - Miyano, Satoru
AU - Tsuzuki, Teruhisa
AU - Hanaoka, Fumio
AU - Yoshioka, Ken ichi
N1 - Funding Information:
We thank Drs. R. D. Wood, F. Esashi, P. Hsieh, H. Saya, N. Onishi, B. Shiotani, and H. Teraoka for critical discussion of this manuscript; Drs. T. Shibata and F. Hosoda for support with Illumina sequencing; Dr. S. Dobashi for technical support; Mr. Y. Sato for support in immunofluorescence by Zeiss LSM880; Dr. Y. Shiraishi for support in TCGA data analyses. This study was supported by Grant-in-Aid for Scientific Research on Innovative Areas (13H04908), the MEXT/JSPS KAKENHI (20770136), and the National Cancer Center Research and Development Fund (23-C-10).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071751323&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071751323&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-11760-2
DO - 10.1038/s41467-019-11760-2
M3 - Article
C2 - 31477700
AN - SCOPUS:85071751323
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3925
ER -
