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MCM 8 and  MCM 9 are paralogues of the  MCM 2‐7 eukaryotic  DNA  replication helicase proteins and play a crucial role in a homologous recombination‐mediated repair process to resolve replication stress by fork stalling. Thus, deficiency of MCM8‐9 sensitizes cells to replication stress caused, for example, by platinum compounds that induce interstrand cross‐links. It is suggested that cancer cells undergo more replication stress than normal cells due to hyperstimulation of growth. Therefore, it is possible that inhibiting MCM8‐9 selectively hypersensitizes cancer cells to platinum compounds and poly( ADP ‐ribose) polymerase inhibitors, both of which hamper replication fork progression. Here, we inhibited MCM8‐9 in transformed and nontransformed cells and examined their sensitivity to cisplatin and olaparib. We found that knockout of  MCM 9 or knockdown of  MCM 8 selectively hypersensitized transformed cells to cisplatin and olaparib. In agreement with reported findings,  RAS ‐ and human papilloma virus type 16 E7‐mediated transformation of human fibroblasts increased replication stress, as indicated by induction of multiple  DNA  damage responses (including formation of Rad51 foci). Such replication stress induced by oncogenes was further increased by knockdown of  MCM 8, providing a rationale for cancer‐specific hypersensitization to cisplatin and olaparib. Finally, we showed that knocking out  MCM 9 increased the sensitivity of  HCT 116 xenograft tumors to cisplatin. Taken together, the data suggest that conceptual MCM8‐9 inhibitors will be powerful cancer‐specific chemosensitizers for platinum compounds and poly( ADP ‐ribose) polymerase inhibitors, thereby opening new avenues to the design of novel cancer chemotherapeutic strategies.

Inhibiting the MCM8‐9 complex selectively sensitizes cancer cells to cisplatin and olaparib