MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells

Takeuchi, Y.; Murayama, T.; Yamawaki, K.; Natsume, T.; Marcela, R.-C. N.; Nishimura, T.; Kogure, Y.; Nakata, A.; Tominaga, K.; Sasahara, A.; Yano, M.; Ishikawa, S.; Ohta, T.; Ikeda, K.; Horie-Inoue, K.; Inoue, S.; Seki, M.; Suzuki, Y.; Sugano, S.; Enomoto, T.; Tanabe, M.; Tada, K.-i.; Kanemaki, M.; Okamoto, K.; Tojo, A.; Gotoh, N.

doi:10.1101/2020.07.20.211961

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bioRxiv · 10.1101/2020.07.20.211961

MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells

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Abstract

Cancer stem-like cells (CSCs) are responsible for the drug resistance of tumors and recurrence while they experience DNA replication stress. However, the underlying mechanisms that cause DNA replication stress in CSCs and how they compensate for this stress remain unclear. Here we provide evidence that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), which is a firing (activating) factor of the DNA replication origins, to compensate for the DNA replication stress. Expression levels of MCM10 are upregulated in CSCs and maintained by c-Myc. c-Myc-dependent collisions may take place between RNA transcription and DNA replication machinery in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to the collisions to ensure replication progression. Moreover, patient-derived breast CSCs were dependent on MCM10 for their maintenance even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. In addition, MCM10 depletion decreased the growth of cancer cells but not normal cells. Therefore, MCM10 is likely to robustly compensate for DNA replication stress and facilitate genome duplication in the S-phase in cancer cells, which is more pronounced in CSCs. We provide a preclinical rationale to target the c-Myc-MCM10 axis to prevent drug resistance and recurrence.

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Takeuchi, Y., Murayama, T., Yamawaki, K., Natsume, T., Marcela, R.-C. N., Nishimura, T., Kogure, Y., Nakata, A., Tominaga, K., Sasahara, A., Yano, M., Ishikawa, S., Ohta, T., Ikeda, K., Horie-Inoue, K., Inoue, S., Seki, M., Suzuki, Y., Sugano, S., Enomoto, T., Tanabe, M., Tada, K.-i., Kanemaki, M., Okamoto, K., Tojo, A., Gotoh, N.. 2020-07-21. MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells. https://doi.org/10.1101/2020.07.20.211961

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