Regulation of MCM2-7 function

Abstract

Recently published structural and functional analyses of the CMG complex have provided insight into the mechanism of its DNA helicase function and into the distinct roles of its central six component proteins MCM2-MCM7 (MCM2-7). To activate CMG helicase, the two protein kinases CDK and DDK, as well as MCM10, are required. In addition to the initiation of DNA replication, MCM function must be regulated at the DNA replication steps of elongation and termination. Polyubiquitylation of MCM7 is involved in terminating MCM function. Reinitiation of DNA replication in a single cell cycle, which is prevented mainly by CDK, is understood at the molecular level. MCM2-7 gene expression is regulated during cellular aging and the cell cycle, and the expression depends on oxygen concentration. These regulatory processes have been described recently. Genomic structural alteration, which is an essential element in cancer progression, is mainly generated by disruptions of DNA replication fork structures. A point mutation in MCM4 that disturbs MCM2-7 function results in genomic instability, leading to the generation of cancer cells. In this review, I focus on the following points: 1) function of the MCM2-7 complex, 2) activation of MCM2-7 helicase, 3) regulation of MCM2-7 function, 4) MCM2-7 expression, and 5) the role of MCM mutation in cancer progression.

MCMs in Cancer: Prognostic Potential and Mechanisms

“…F345I mutation weakens the interaction with MCM6 [90]. G364R mutation was detected in skin cancer cells, and G486D mutation was detected in endometrial cancer cells [1].…”

“…Minichromosome maintenance proteins (MCMs) were first identified in Saccharomyces cerevisiae as imperative factors in the maintenance of extrachromosomal DNA [1]. In eukaryotic cells, MCM2-7 form a hetero-hexameric AAA+ ATPase.…”

“…In the CMG complex, MCM2/5 and MCM3/5 correspondingly interact with Cdc45 and GINS, and the association is stabilized by MCM10; MCM10 also helps activate the helicase activity of MCM2-7 complex and stimulates elongation [12,15,20,21]. During elongation, MCM4/6/7 is directly involved in the translocation of CMG complex from the origin along the single-strand DNA in the MCM2-7COMPLEX, and MCM2 can be dephosphorylated by PTEN to restrict replication fork progression [1,11]. MCM2/4/5/6/7 correlatedly shifted and formed a tight cluster [23].…”

Working on Genomic Stability: From the S-Phase to Mitosis

“…Replication origin licensing takes place from late mitosis until the end of G1 by loading double MCM2-7 hexamers at origins and is a highly CDK activity-dependent process (Table 1) [20][21][22]; for a recent review on origin licensing see [23]. In this way, at the beginning of the S-phase, MCM hexamers are activated at hundreds of thousands of origins distributed in a non-random way throughout the genome forming the ring of the replicative helicase that unwinds the DNA ahead of DNA polymerase [20,[24][25][26]. It has been proposed that S-phase initiation is inhibited in many cells until enough origins are licensed by a p53-dependent "origin licensing checkpoint" [26][27][28][29].…”

Changes in MCM2–7 proteins at senescence

“…Other replication proteins including DNA polymerase ε assemble at the origins in the presence of CDK (Araki, 2011). Several lines of evidence suggest that the CMG complex, which is MCM2-7 complexed with CDC45 and the GINS complex, functions as a replicative DNA helicase (Labib and Gambus, 2007;Ishimi, 2018). Recent reports indicate that the levels of MCM2-7 proteins are down-regulated in senescent cells (Dumit et al, 2014;Flach et al, 2014) and also in quiescent cells (Namdar and Kearsey, 2006).…”