How and why multiple MCMs are loaded at origins of DNA replication

Abstract

Recent work suggests that DNA replication origins are regulated by the number of multiple Mini-Chromosome Maintenance (MCM) complexes loaded. Origins are defined by the loading of MCM - the replicative helicase which initiates DNA replication and replication kinetics determined by origin’s location and firing times. However, activation of MCM is heterogeneous; different origins firing at different times in different cells. Also, more MCMs are loaded in G1 than are used in S phase. These aspects of MCM biology are explained by the observation that multiple MCMs are loaded at origins. Having more MCMs at early origins makes them more likely to fire, effecting differences in origin efficiency that define replication timing. Nonetheless, multiple MCM loading raises new questions, such as how they are loaded, where these MCMs reside at origins and how their presence affects replication timing. In this review, we address these questions and discuss future avenues of research.

Competition for MCM Loading at Origins Establishes Replication Timing Patterns

“…b) For acute down-regulation of MCM, yFS1059 cultures were arrested at G1/S using α-factor as outlined in Figure 1a, washed, then serially diluted on YPD plates with or without 100 mM HU. Comparison of MCM signal at origins between the 0 µM auxin condition in this study and other publications (Das et al, 2016, DePicoli et al, 2012. c) Genome-wide replication timing correlation in 1 kb windows between the 0 µM auxin condition in this study and Mueller et al, 2012.…”

“…(Figure 5a -yFS1075). b) Comparison of MCM signal at origins between the (-) galactose condition in this study (yFS1075 strain) and other publications (Das et al, 2016, DePicoli et al, 2012. c) Replication timing correlation between the (-) galactose condition (yFS1075 strain) and: i) 0 µM auxin condition for ARS origins, and ii) genome-wide 1 kb windows from Mueller et al, 2012.…”

“…Alternatively, in a multiple-MCM scenario, more than one MCM double-hexamer complex can be loaded at a single origin, so MCM occupancy can range from 0 to many. Both single-and multiple-MCM scenarios have been proposed (Das et al, 2015;Foss et al, 2020;de Moura et al, 2010;Das and Rhind, 2016;Yang et al, 2010).…”

“…b) Trep values of ARS-annotated origins for untreated cells are plotted against values observed for 30 µM and 500 µM auxin treatments. c) Correlation between MCM signal and replication timing for origins that are not known to be affected by specific replication timing control factors(Das et al 2016). d) Correlation between delay in replication timing as a result of auxin treatment and reduction in MCM signal, for origins plotted in c).…”

Minichromosome maintenance protein 2 correlates with the malignant status and regulates proliferation and cell cycle in lung squamous cell carcinoma

“…Minichromosome maintenance protein (MCM) family is composed of six related proteins (MCM2–MCM7), which were originally identified in yeast to activate DNA replication. 11 , 12 Closure of the MCM2/5 gate is required to activate DNA unwinding and elongation. 13 Upon S-phase entry, several regulatory cyclin-dependent kinases and DBF4-dependent kinase activate MCM2–MCM7 by enabling the loading of the key accessory factors CDC45 and GINS that in combination with MCM2–MCM7 form the CMG complex.…”