Epigenetically-inherited centromere and neocentromere DNA replicates earliest in S-phase.
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.
Koren
Amnon
A
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.
Tsai
Hung-Ji
HJ
Tirosh
Itay
I
Burrack
Laura S
LS
Barkai
Naama
N
Berman
Judith
J
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
D004271:DNA, Fungal
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