Correction: 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. for innovative investigations to NB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

[1]  N. Barkai,et al.  MRC1-dependent scaling of the budding yeast DNA replication timing program. , 2010, Genome research.

[2]  S. Henikoff,et al.  Major Evolutionary Transitions in Centromere Complexity , 2009, Cell.

[3]  J. Berman,et al.  Neocentromeres Form Efficiently at Multiple Possible Loci in Candida albicans , 2009, PLoS genetics.

[4]  R. Siddharthan,et al.  Rapid evolution of Cse4p-rich centromeric DNA sequences in closely related pathogenic yeasts, Candida albicans and Candida dubliniensis , 2008, Proceedings of the National Academy of Sciences.

[5]  G. Karpen,et al.  Epigenetic regulation of centromeric chromatin: old dogs, new tricks? , 2008, Nature Reviews Genetics.

[6]  Mikhail S. Gelfand,et al.  Identification of replication origins in prokaryotic genomes , 2008, Briefings Bioinform..

[7]  Owen J. Marshall,et al.  Neocentromeres: new insights into centromere structure, disease development, and karyotype evolution. , 2008, American journal of human genetics.

[8]  Adam P. Rosebrock,et al.  Checkpoint independence of most DNA replication origins in fission yeast , 2007, BMC Molecular Biology.

[9]  Yuki Ogiyama,et al.  Biphasic incorporation of centromeric histone CENP-A in fission yeast. , 2007, Molecular biology of the cell.

[10]  K. Ekwall.  Epigenetic control of centromere behavior. , 2007, Annual review of genetics.

[11]  M. Baum,et al.  Centromere size and position in Candida albicans are evolutionarily conserved independent of DNA sequence heterogeneity , 2007, Molecular Genetics and Genomics.

[12]  Katsuhiko Shirahige,et al.  Genome‐wide localization of pre‐RC sites and identification of replication origins in fission yeast , 2007, The EMBO journal.

[13]  D. Moazed,et al.  Centromere Assembly and Propagation , 2007, Cell.

[14]  Jürg Bähler,et al.  Genome‐wide characterization of fission yeast DNA replication origins , 2006, The EMBO journal.

[15]  M. Baum,et al.  Formation of functional centromeric chromatin is specified epigenetically in Candida albicans , 2006, Proceedings of the National Academy of Sciences.

[16]  Esther Rheinbay,et al.  Phylogenetic and structural analysis of centromeric DNA and kinetochore proteins , 2006, Genome Biology.

[17]  David Collingwood,et al.  Genomic mapping of single-stranded DNA in hydroxyurea-challenged yeasts identifies origins of replication , 2006, Nature Cell Biology.

[18]  M. Baum,et al.  Centromeric DNA sequences in the pathogenic yeast Candida albicans are all different and unique. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  B. Dujon,et al.  Genome evolution in yeasts , 2004, Nature.

[20]  J. Huberman,et al.  Early-replicating heterochromatin. , 2003, Genes & development.

[21]  J. Carbon,et al.  The CENP-A homolog CaCse4p in the pathogenic yeast Candida albicans is a centromere protein essential for chromosome transmission , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Newlon,et al.  Yeast origins establish a strand bias for replicational mutagenesis. , 2002, Molecular cell.

[23]  John J. Wyrick,et al.  Genome-Wide Distribution of ORC and MCM Proteins in S. cerevisiae: High-Resolution Mapping of Replication Origins , 2001, Science.

[24]  Ronald W. Davis,et al.  Replication dynamics of the yeast genome. , 2001, Science.

[25]  G. Karpen,et al.  Centromere identity in Drosophila is not determined in vivo by replication timing , 2001, The Journal of cell biology.

[26]  S. Henikoff,et al.  The Centromere Paradox: Stable Inheritance with Rapidly Evolving DNA , 2001, Science.

[27]  Gary H. Karpen,et al.  Determining centromere identity: cyclical stories and forking paths , 2001, Nature Reviews Genetics.

[28]  S. Henikoff,et al.  Centromeres Are Specialized Replication Domains in Heterochromatin , 2001, The Journal of cell biology.

[29]  S. Casaregola,et al.  Only centromeres can supply the partition system required for ARS function in the yeast Yarrowia lipolytica. , 2001, Journal of molecular biology.

[30]  K. Sullivan,et al.  Chromatin Assembly at Kinetochores Is Uncoupled from DNA Replication , 2000, The Journal of cell biology.

[31]  M. Yanagida,et al.  Requirement of Mis6 centromere connector for localizing a CENP-A-like protein in fission yeast. , 2000, Science.

[32]  S. Henikoff,et al.  Heterochromatic deposition of centromeric histone H3-like proteins. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S Henikoff,et al.  Something from nothing: the evolution and utility of satellite repeats. , 1998, Trends in genetics : TIG.

[34]  D. Rickwood,et al.  Cell and Molecular Biology , 1998, The Journal of Steroid Biochemistry and Molecular Biology.

[35]  P. Fournier,et al.  Colocalization of centromeric and replicative functions on autonomously replicating sequences isolated from the yeast Yarrowia lipolytica. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[36]  W. L. Fangman,et al.  The localization of replication origins on ARS plasmids in S. cerevisiae , 1987, Cell.

[37]  B. E. Black,et al.  The epigenetic basis for centromere identity. , 2009, Progress in molecular and subcellular biology.

[38]  H. Rahn,et al.  Replication of centromeric heterochromatin in mouse fibroblasts takes place in early, middle, and late S phase , 2005, Histochemistry and Cell Biology.