Role of MCM2-7 protein phosphorylation in human cancer cells

Abstract

A heterohexameric complex composed of minichromosome maintenance protein 2-7 (MCM2-7), which acts as a key replicative enzyme in eukaryotes, is crucial for initiating DNA synthesis only once per cell cycle. The MCM complex remains inactive through the G1 phase, until the S phase, when it is activated to initiate replication. During the transition from the G1 to S phase, the MCM undergoes multisite phosphorylation, an important change that promotes subsequent assembly of other replisome members. Phosphorylation is crucial for the regulation of MCM activity and function. MCMs can be phosphorylated by multiple kinases and these phosphorylation events are involved not only in DNA replication but also cell cycle progression and checkpoint response. Dysfunctional phosphorylation of MCMs appears to correlate with the occurrence and development of cancers. In this review, we summarize the currently available data regarding the regulatory mechanisms and functional consequences of MCM phosphorylation and seek the probability that protein kinase inhibitor can be used therapeutically to target MCM phosphorylation in cancer.

Keywords: Cell cycle; Checkpoint response; DNA replication; MCM; Phosphorylation.

Fig. 1

Schematic diagram summarizing the roles of MCM phosphorylation mediated by three classes of kinases Cdc7, Cdk and ATM/ATR. Although many functional crosstalks exist between MCM kinases-mediated phosphorylation events, evidence shows that Cdc7-dependent MCM phosphorylation primarily promotes the initiation of DNA replication, Cdk-dependent MCM phosphorylation mainly contributes to cell cycle progression regulation, and ATM/ATR-dependent MCM phosphorylation primarily responds to replication stress. MCM phosphorylation contributes to these various functions primarily by affecting MCM complex formation, chromatin binding, and (or) helicase activity

Fig. 2

Roles of MCM phosphorylation mediated by p56Lyn, Akt and ILK in cancer development. Phosphorylation of MCM7 mediated by EGFR-p56^Lyn and RACK1-Akt promotes MCM complex assembly and chromatin loading, therefore enhancing DNA synthesis and cancer cell proliferation. In contrast, MCM7 phosphorylation mediated by ITGA7-ILK axis reduces MCM7 chromatin association, inhibiting cell growth