The Mcm2-7 Replicative Helicase: A Promising Chemotherapeutic Target

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.

Roles of pRB in the Regulation of Nucleosome and Chromatin Structures

“…Through the physical interaction with these protein factors, pRB is involved in not only local gene promoter inactivation but also global epigenetic control of cellular senescence [21] and differentiation [22]. Furthermore, pRB was recently shown to play a role in DNA replication during the S phase and G2/M phases via interactions with regulator proteins for DNA replication [12, 23], chromatin condensation [24–27], and mitotic spindle formation [28]. Understandably, cellular events, such as G0/G1 maintenance, DNA replication, and mitosis progression, require drastic nuclear structural changes and chromosomal rearrangement.…”

Comparison between immunohistochemical expression of Ki-67 and MCM-3 in major salivary gland epithelial tumors in children and adolescents. Preliminary study

“…oral dysplasia [24]. The MCM complex may also offer an alternative target for blocking the proliferation of cancerous and precancerous tumor cells and thus also oncological drug development for various tumors, as suggested by Simon et al [25].…”

Regulation of Mammalian DNA Replication via the Ubiquitin-Proteasome System

“…On one hand, failure of the ordered assembly of pre-RCs on sufficient origins of replications in late M and in G1 inhibits cell proliferation. This is demonstrated by the fact that targeted knockout or knockdown of many of the pre-RC components in various eukaryotes interferes with viability, and thus some of these components, e.g., the MCM2-7 helicases, are considered promising chemotherapeutic targets in cancer (Lei 2005; Simon and Schwacha 2014). On the other hand, excessive origin licensing can result in DNA rereplication, which is deleterious to cells owing to the accumulation of replication intermediates and collapsed replication forks (Abbas et al 2013).…”