As a crucial component of DNA replication licensing system, minichromosome maintenance (MCM) 2–7 complex acts as the eukaryotic DNA replicative helicase. The six related MCM proteins form a heterohexamer and bind with ORC, CDC6, and Cdt1 to form the prereplication complex. Although the MCMs are well known as replicative helicases, their overabundance and distribution patterns on chromatin present a paradox called the “MCM paradox.” Several approaches had been taken to solve the MCM paradox and describe the purpose of excess MCMs distributed beyond the replication origins. Alternative functions of these MCMs rather than a helicase had also been proposed. This review focuses on several models and concepts generated to solve the MCM paradox coinciding with their helicase function and provides insight into the concept that excess MCMs are meant for licensing dormant origins as a backup during replication stress. Finally, we extend our view towards the effect of alteration of MCM level. Though an excess MCM constituent is needed for normal cells to withstand stress, there must be a delineation of the threshold level in normal and malignant cells. This review also outlooks the future prospects to better understand the MCM biology. 1. Introduction In early 1980s, minichromosome maintenance (MCM) proteins were first identified in budding yeast Saccharomyces cerevisiae [1]. These mutant variants were defective in maintenance of minichromosome, a plasmid with a cloned centromere and replication origin [2, 3]. MCM proteins were thus found to have essential roles in DNA replication [4, 5]. Subsequent identification of proteins with a particular identical sequence termed “MCM box” [6] leads to the constitution of a protein family, the MCM family. The family consists of at least 6 homologues, MCM 2–7 [1], which is directly involved in eukaryotic DNA replication [7]. MCMs remain at the centre of interest of biochemists, geneticists, and cancer biologists since 30 years of their identification. The studies provide good knowledge of MCM structure, function, particular role in DNA replication, and abnormalities leading to cancer. On the other hand, some paradoxes came forward with the advancement of studies regarding the function of MCMs in DNA replication. It has been found that the MCM hexamers are loaded in excess onto chromatin and distributed on the locations distant from the origins. Solving the paradox known as the “MCM paradox” is challenging to the scientific community. In this review we have discussed the role of MCMs in DNA replication, concepts generated to
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