Abstract
To complete the duplication of large genomes efficiently, mechanisms have evolved that coordinate DNA unwinding with DNA synthesis and provide quality control measures prior to cell division. Minichromosome maintenance protein 10 (Mcm10) is a conserved component of the eukaryotic replisome that contributes to this process in multiple ways. Mcm10 promotes the initiation of DNA replication through direct interactions with the cell division cycle 45 (Cdc45)-minichromosome maintenance complex proteins 2-7 (Mcm2-7)-go-ichi-ni-san GINS complex proteins, as well as single- and double-stranded DNA. After origin firing, Mcm10 controls replication fork stability to support elongation, primarily facilitating Okazaki fragment synthesis through recruitment of DNA polymerase-α and proliferating cell nuclear antigen. Based on its multivalent properties, Mcm10 serves as an essential scaffold to promote DNA replication and guard against replication stress. Under pathological conditions, Mcm10 is often dysregulated. Genetic amplification and/or overexpression of MCM10 are common in cancer, and can serve as a strong prognostic marker of poor survival. These findings are compatible with a heightened requirement for Mcm10 in transformed cells to overcome limitations for DNA replication dictated by altered cell cycle control. In this review, we highlight advances in our understanding of when, where and how Mcm10 functions within the replisome to protect against barriers that cause incomplete replication.
Highlights
Efficient Replication of Large Eukaryotic GenomesAt a speed of 1.5 kb per minute, it would take approximately 60 days to duplicate one copy of the human genome if a single, unidirectional fork replicated each chromosome
To complete the duplication of large genomes efficiently, mechanisms have evolved that coordinate DNA unwinding with DNA synthesis and provide quality control measures prior to cell division
Replication begins with the loading of the catalytic core of the replicative helicase, which is composed of the minichromosome maintenance complex proteins 2-7 (Mcm2-7)
Summary
At a speed of 1.5 kb per minute, it would take approximately 60 days to duplicate one copy of the human genome if a single, unidirectional fork replicated each chromosome. The first step, origin licensing, occurs via loading of Mcm double hexamers onto double-stranded DNA (dsDNA) [17,18,19,20] This is achieved during late mitosis and G1-phase through the coordinated action of the origin recognition complex (ORC), cell division cycle 6 protein (Cdc6), and Cdc10-dependent transcript 1 (Cdt1) to complete assembly of the pre-replication complex (pre-RC) [19,20,21,22]. Once a sufficiently high number of replication origins have been licensed [23], cells prohibit formation of additional pre-RCs and commit to the second stage of DNA replication, origin firing and DNA synthesis [18,24,25,26] To this end, the helicase co-factors cell division cycle. We focus on Mcm and how it ensures timely and accurate completion of DNA replication
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