A Link between ORC-origin binding mechanisms and origin activation time revealed in budding yeast.

Timothy Hoggard, Erika Shor, Carolin A Müller, Conrad A Nieduszynski, Catherine A Fox

PLoS Genet. (2013), 9(9):e1003798PDF | PubMed | PubMed Central | PLoS Genet.

Eukaryotic DNA replication origins are selected in G1-phase when the origin recognition complex (ORC) binds chromosomal positions and triggers molecular events culminating in the initiation of DNA replication (a.k.a. origin firing) during S-phase. Each chromosome uses multiple origins for its duplication, and each origin fires at a characteristic time during S-phase, creating a cell-type specific genome replication pattern relevant to differentiation and genome stability. It is unclear whether ORC-origin interactions are relevant to origin activation time. We applied a novel genome-wide strategy to classify origins in the model eukaryote Saccharomyces cerevisiae based on the types of molecular interactions used for ORC-origin binding. Specifically, origins were classified as DNA-dependent when the strength of ORC-origin binding in vivo could be explained by the affinity of ORC for origin DNA in vitro, and, conversely, as 'chromatin-dependent' when the ORC-DNA interaction in vitro was insufficient to explain the strength of ORC-origin binding in vivo. These two origin classes differed in terms of nucleosome architecture and dependence on origin-flanking sequences in plasmid replication assays, consistent with local features of chromatin promoting ORC binding at 'chromatin-dependent' origins. Finally, the 'chromatin-dependent' class was enriched for origins that fire early in S-phase, while the DNA-dependent class was enriched for later firing origins. Conversely, the latest firing origins showed a positive association with the ORC-origin DNA paradigm for normal levels of ORC binding, whereas the earliest firing origins did not. These data reveal a novel association between ORC-origin binding mechanisms and the regulation of origin activation time.

Our publications

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DNA replication timing influences gene expression level.
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J. Cell Biol., 216(7):1907-1914

Deep functional analysis of synII, a 770-kilobase synthetic yeast chromosome.
Shen et al. (2017)
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Discovery of an Unconventional Centromere in Budding Yeast Redefines Evolution of Point Centromeres.
Kobayashi et al. (2015)
Curr. Biol., 25(15):2026-33

A global profile of replicative polymerase usage.
Daigaku et al. (2015)
Nat. Struct. Mol. Biol., 22(3):192-8


The dynamics of genome replication using deep sequencing.
Müller et al. (2014)
Nucleic Acids Res., 42(1):e3


High-resolution replication profiles define the stochastic nature of genome replication initiation and termination.
Hawkins et al. (2013)
Cell Rep, 5(4):1132-41

Accelerated growth in the absence of DNA replication origins.
Hawkins et al. (2013)
Nature, 503(7477):544-547

Stochastic association of neighboring replicons creates replication factories in budding yeast.
Saner et al. (2013)
J. Cell Biol., 202(7):1001-1012

A Link between ORC-origin binding mechanisms and origin activation time revealed in budding yeast.
Hoggard et al. (2013)
PLoS Genet., 9(9):e1003798

Replisome stall events have shaped the distribution of replication origins in the genomes of yeasts.
Newman et al. (2013)
Nucleic Acids Res., 41(21):9705-18

Avoiding chromosome pathology when replication forks collide.
Rudolph et al. (2013)
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Kinetochores coordinate pericentromeric cohesion and early DNA replication by cdc7-dbf4 kinase recruitment.
Natsume et al. (2013)
Mol. Cell, 50(5):661-74

High quality de novo sequencing and assembly of the Saccharomyces arboricolus genome.
Liti et al. (2013)
BMC Genomics, 14():69


Mathematical modeling of genome replication.
Retkute et al. (2012)
Phys Rev E Stat Nonlin Soft Matter Phys, 86(3 Pt 1):031916

Conservation of replication timing reveals global and local regulation of replication origin activity.
Müller & Nieduszynski (2012)
Genome Res., 22(10):1953-62

A putative homologue of CDC20/CDH1 in the malaria parasite is essential for male gamete development.
Guttery et al. (2012)
PLoS Pathog., 8(2):e1002554


OriDB, the DNA replication origin database updated and extended.
Siow et al. (2011)
Nucleic Acids Res., 40(Database issue):D682-6

Dynamics of DNA replication in yeast.
Retkute et al. (2011)
Phys. Rev. Lett., 107(6):068103

Comparative functional genomics of the fission yeasts.
Rhind et al. (2011)
Science, 332(6032):930-6

From sequence to function: Insights from natural variation in budding yeasts.
Nieduszynski & Liti (2011)
Biochim. Biophys. Acta, 1810(10):959-66


Mathematical modelling of whole chromosome replication.
de Moura et al. (2010)
Nucleic Acids Res., 38(17):5623-33


The origin recognition complex interacts with a subset of metabolic genes tightly linked to origins of replication.
Shor et al. (2009)
PLoS Genet., 5(12):e1000755

Detection of replication origins using comparative genomics and recombinational ARS assay.
Nieduszynski & Donaldson (2009)
Methods Mol. Biol., 521():295-313


Analysis of chromosome III replicators reveals an unusual structure for the ARS318 silencer origin and a conserved WTW sequence within the origin recognition complex binding site.
Chang et al. (2008)
Mol. Cell. Biol., 28(16):5071-81


OriDB: a DNA replication origin database.
Nieduszynski et al. (2006)
Nucleic Acids Res., 35(Database issue):D40-6

Genome-wide identification of replication origins in yeast by comparative genomics.
Nieduszynski et al. (2006)
Genes Dev., 20(14):1874-9


The requirement of yeast replication origins for pre-replication complex proteins is modulated by transcription.
Nieduszynski et al. (2005)
Nucleic Acids Res., 33(8):2410-20


The cyclin A1-CDK2 complex regulates DNA double-strand break repair.
Müller-Tidow et al. (2004)
Mol. Cell. Biol., 24(20):8917-28

Cyclin A1 protein shows haplo-insufficiency for normal fertility in male mice.
van der Meer et al. (2004)
Reproduction, 127(4):503-11


Whole-genome analysis of animal A- and B-type cyclins.
Nieduszynski et al. (2002)
Genome Biol., 3(12):RESEARCH0070

Ku complex controls the replication time of DNA in telomere regions.
Cosgrove et al. (2002)
Genes Dev., 16(19):2485-90

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