title: Replication timing is regulated by the number of MCMs loaded at origins.
abstract: Replication timing is a crucial aspect of genome regulation that is strongly correlated with chromatin structure, gene expression, DNA repair, and genome evolution. Replication timing is determined by the timing of replication origin firing, which involves activation of MCM helicase complexes loaded at replication origins. Nonetheless, how the timing of such origin firing is regulated remains mysterious. Here, we show that the number of MCMs loaded at origins regulates replication timing. We show for the first time in vivo that multiple MCMs are loaded at origins. Because early origins have more MCMs loaded, they are, on average, more likely to fire early in S phase. Our results provide a mechanistic explanation for the observed heterogeneity in origin firing and help to explain how defined replication timing profiles emerge from stochastic origin firing. These results establish a framework in which further mechanistic studies on replication timing, such as the strong effect of heterochromatin, can be pursued.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
authors.forename: Shankar P
authors.initials: SP
authors.lastname: Das
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
authors.forename: Tyler
authors.initials: T
authors.lastname: Borrman
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
authors.forename: Victor W T
authors.initials: VW
authors.lastname: Liu
authors.affiliation: Department of Physics, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Scott C-H
authors.initials: SC
authors.lastname: Yang
authors.affiliation: Department of Physics, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Bechhoefer
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rhind
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004261:DNA Replication; D042522:DNA Replication Timing; D059014:High-Throughput Nucleotide Sequencing; D064110:Minichromosome Maintenance Proteins / Q000378:metabolism*; D011485:Protein Binding; D018741:Replication Origin; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: D064110:Minichromosome Maintenance Proteins