MCM10: One tool for all—Integrity, maintenance and damage control

Abstract

Minichromsome maintenance protein 10 (Mcm10) is an essential replication factor that is required for the activation of the Cdc45:Mcm2-7:GINS helicase. Mcm10's ability to bind both ds and ssDNA appears vital for this function. In addition, Mcm10 interacts with multiple players at the replication fork, including DNA polymerase-α and proliferating cell nuclear antigen with which it cooperates during DNA elongation. Mcm10 lacks enzymatic function, but instead provides the replication apparatus with an oligomeric scaffold that likely acts in the coordination of DNA unwinding and DNA synthesis. Not surprisingly, loss of Mcm10 engages checkpoint, DNA repair and SUMO-dependent rescue pathways that collectively counteract replication stress and chromosome breakage. Here, we review Mcm10's structure and function and explain how it contributes to the maintenance of genome integrity.

MicroRNA-215 Regulates Fibroblast Function: Insights from a Human Fibrotic Disease

“…In replication initiation, Mcm10 binds to single-stranded DNA (ssDNA) and promotes helicase activation, 49 and may recruit DNA polymerase-a primase to aid DNA elongation. 50 In view of its function in DNA replication, defects of Mcm10 may result in defective G1/S progression.…”

Slx5/Slx8 Promotes Replication Stress Tolerance by Facilitating Mitotic Progression

“…Heat-induced depletion of Mcm10 causes replication stress displaying the typical hallmarks of Rad53 phosphorylation and PCNA ubiquitination (Becker et al, 2014). SGA analysis identified SLX5 and SLX8 as top hits that exhibited synthetic sickness with the mcm10-1 allele at 30°C (Thu and Bielinsky, 2013, 2014). We validated the SGA results in a different genetic background and found that an approximately 100-fold growth defect in mcm10-1 slx5Δ mutants was apparent at 33°C compared to either single mutant (Figure 1A).…”

“…During the subsequent elongation step, Mcm10 is anchored to the Mcm2-7 complex, which comprises the core of the replicative Cdc45:Mcm2-7:GINS (CMG) helicase. It transiently interacts with DNA polymerase-α/primase and proliferating cell nuclear antigen (PCNA) both of which cycle on and off DNA during lagging strand synthesis (Thu and Bielinsky, 2014). Accordingly, depletion of Mcm10 compromises fork elongation, most notably at fragile sites of the human genome (Miotto et al, 2014).…”

“…A recent synthetic genetic array analysis (SGA) of mcm10-1 , a temperature-sensitive mutant strain of Saccharomyces cerevisiae , revealed a strong negative genetic interaction between genes encoding the small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligase (STUbL) complex Slx5/8 (Slx5/8; synthetically lethal with sgs1 ) and mcm10-1 (Thu and Bielinsky, 2013, 2014). The Slx5/8 heterodimer functions as an E3 ubiquitin ligase responsible for the turnover of poly-sumoylated proteins, and has been implicated in the maintenance of genome integrity (Galanty et al, 2012; Vyas et al, 2013; Xie et al, 2007; Yin et al, 2012).…”

“…We chose mcm10 mutants as a genetic model for replication stress, since these cells are synthetically sick with deletions of SLX5 and SLX8 (Thu and Bielinsky, 2013, 2014). We analyzed the SUMO proteome and identified proteins potentially regulated by Slx5/8.…”