Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro
Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro
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DOI：
10.1038/s41467-019-11760-2
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发表时间：
2019-09-02
影响因子：
16.6
通讯作者：
Yoshioka, Ken-ichi
中科院分区：
文献类型：
--
作者：
Matsuno, Yusuke;Atsumi, Yuko;Yoshioka, Ken-ichi
错配修复（MMR）缺陷型癌症的特征在于微卫星不稳定性（MSI）和超突变。然而，目前尚不清楚MSI和超突变是如何产生并促进癌症发展的。在这里，我们表明，MSI和hypermutation是由MMR缺陷背景下的复制应激触发的，使携带ARF/p53模块突变的细胞和对抗癌药物喜树碱具有抗性的细胞能够克隆扩增。虽然复制应激相关的DNA双链断裂（DSB）在MMR-熟练的背景下引起染色体不稳定性（CIN），但它们在MMR-缺陷的背景下通过PARP介导的修复途径诱导MSI伴随CIN的抑制。这与通过染色体缺失和碱基取代诱导突变有关，包括ARF/p53模块中的癌症驱动突变。与ARF/p53模块突变相关的MMR缺陷小鼠胚胎成纤维细胞（MEFs）的永生化比野生型MEFs的永生化效率高60倍。因此，复制应激触发的MSI和超突变有效地导致具有废除的防御系统的细胞的克隆扩增。
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 similar to 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.