title: Epigenetically-inherited centromere and neocentromere DNA replicates earliest in S-phase.
abstract: Eukaryotic centromeres are maintained at specific chromosomal sites over many generations. In the budding yeast Saccharomyces cerevisiae, centromeres are genetic elements defined by a DNA sequence that is both necessary and sufficient for function; whereas, in most other eukaryotes, centromeres are maintained by poorly characterized epigenetic mechanisms in which DNA has a less definitive role. Here we use the pathogenic yeast Candida albicans as a model organism to study the DNA replication properties of centromeric DNA. By determining the genome-wide replication timing program of the C. albicans genome, we discovered that each centromere is associated with a replication origin that is the first to fire on its respective chromosome. Importantly, epigenetic formation of new ectopic centromeres (neocentromeres) was accompanied by shifts in replication timing, such that a neocentromere became the first to replicate and became associated with origin recognition complex (ORC) components. Furthermore, changing the level of the centromere-specific histone H3 isoform led to a concomitant change in levels of ORC association with centromere regions, further supporting the idea that centromere proteins determine origin activity. Finally, analysis of centromere-associated DNA revealed a replication-dependent sequence pattern characteristic of constitutively active replication origins. This strand-biased pattern is conserved, together with centromere position, among related strains and species, in a manner independent of primary DNA sequence. Thus, inheritance of centromere position is correlated with a constitutively active origin of replication that fires at a distinct early time. We suggest a model in which the distinct timing of DNA replication serves as an epigenetic mechanism for the inheritance of centromere position.
authors.affiliation: Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Amnon
authors.initials: A
authors.lastname: Koren
authors.forename: Hung-Ji
authors.initials: HJ
authors.lastname: Tsai
authors.forename: Itay
authors.initials: I
authors.lastname: Tirosh
authors.forename: Laura S
authors.initials: LS
authors.lastname: Burrack
authors.forename: Naama
authors.initials: N
authors.lastname: Barkai
authors.forename: Judith
authors.initials: J
authors.lastname: Berman
mesh_terms: D002176:Candida albicans / Q000166:cytology / Q000235:genetics* / Q000378:metabolism; D002503:Centromere / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D004271:DNA, Fungal / Q000235:genetics; D044127:Epigenesis, Genetic; D018741:Replication Origin; D016196:S Phase; D012568:Schizosaccharomyces / Q000166:cytology / Q000235:genetics / Q000378:metabolism
chemical_list: D004271:DNA, Fungal
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