Abstract
Numerous eukaryotic replication factors have served as chemotherapeutic targets. One replication factor that has largely escaped drug development is the Mcm2-7 replicative helicase. This heterohexameric complex forms the licensing system that assembles the replication machinery at origins during initiation, as well as the catalytic core of the CMG (Cdc45-Mcm2-7-GINS) helicase that unwinds DNA during elongation. Emerging evidence suggests that Mcm2-7 is also part of the replication checkpoint, a quality control system that monitors and responds to DNA damage. As the only replication factor required for both licensing and DNA unwinding, Mcm2-7 is a major cellular regulatory target with likely cancer relevance. Mutations in at least one of the six MCM genes are particularly prevalent in squamous cell carcinomas of the lung, head and neck, and prostrate, and MCM mutations have been shown to cause cancer in mouse models. Moreover various cellular regulatory proteins, including the Rb tumor suppressor family members, bind Mcm2-7 and inhibit its activity. As a preliminary step toward drug development, several small molecule inhibitors that target Mcm2-7 have been recently discovered. Both its structural complexity and essential role at the interface between DNA replication and its regulation make Mcm2-7 a potential chemotherapeutic target.
Highlights
Misregulated DNA replication is a basic prerequisite for uncontrolled cellular proliferation, and the clinical targeting of eukaryotic replication factors has seen widespread use in cancer treatment
The development of Mcm2-7-specific small molecule inhibitors is at an early stage, and structure-activity relationship of these compounds is poorly understood
Mcm2-7 is a structurally and functionally complex replication factor with a rich binding surface that directs multiple regulatory interactions of cancer significance, including those required for both Rb/E2F signaling as well as DNA replication
Summary
Misregulated DNA replication is a basic prerequisite for uncontrolled cellular proliferation, and the clinical targeting of eukaryotic replication factors has seen widespread use in cancer treatment. Work from budding yeast has shown that a complex containing only the Mcm and 7 subunits is capable of unwinding DNA [25], and biochemical analysis of the corresponding Mcm4/7 ATPase active site demonstrates that it is important for both steady-state ATP hydrolysis and DNA unwinding activities of the Mcm hexamer [19, 23, 24]. Given the likely differential involvement of specific Mcm ATPase active sites in multiple aspects of DNA replication and its regulation, small molecule inhibitors could be profitably identified that selectively target these individual activities. Such inhibitors could prove useful for a variety of research as well as chemotherapy applications. As various alterations in Mcm expression or function are linked to oncogenic DNA replication (e.g., [57]), Mcm is a promising drug target for the development of both general replication inhibitors that stem cellular proliferation, as well as potentially more sophisticated inhibitors that target Mcm in tumor cells (discussed below)
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