Key Points
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Chromosomal DNA is packaged with histones into nucleosomes. Following replication, sister-chromatid segregation is orchestrated to ensure that each daughter cell receives a complete set of chromosomes.
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The centromere is the chromosomal region responsible for formation of the kinetochore, which mediates attachment to spindle microtubules and chromosome movement.
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In organisms with complex centromeres the site of kinetochore assembly is epigenetically determined and is not strictly governed by primary DNA sequence.
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The key determining factor in specifying the site of kinetochore assembly is the deposition of the centromere-specific histone H3 variant CENP-A.
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In tissue-culture cells, new CENP-A is deposited during late mitosis and through G1, independently of DNA replication.
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A portion of the histone fold domain of CENP-A is necessary and sufficient for targeting to centromeres.
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CENP-A nucleosomes depleted during S phase replication are restored later in the cell cycle by de novo deposition into 'gaps' or by replacement of H3 nucleosomes.
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Numerous factors have been identified that are required for CENP-A localization, but the chromatin assembly proteins that are directly required for propagation of CENP-A chromatin are not known.
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Non-coding transcripts and transcription factors are associated with centromeres, and transcription might be linked to CENP-A chromatin assembly in some systems.
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CENP-B binding sites and flanking centric heterochromatin influence the establishment of CENP-A chromatin on naive templates.
Abstract
The assembly of just a single kinetochore at the centromere of each sister chromatid is essential for accurate chromosome segregation during cell division. Surprisingly, despite their vital function, centromeres show considerable plasticity with respect to their chromosomal locations and activity. The establishment and maintenance of centromeric chromatin, and therefore the location of kinetochores, is epigenetically regulated. The histone H3 variant CENP-A is the key determinant of centromere identity and kinetochore assembly. Recent studies have identified many factors that affect CENP-A localization, but their precise roles in this process are unknown. We build on these advances and on new information about the timing of CENP-A assembly during the cell cycle to propose new models for how centromeric chromatin is established and propagated.
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Acknowledgements
The authors thanks members of their laboratories for comments and suggestions. R.C.A. is a Wellcome Trust Principal Research Fellow and his research is supported by the Wellcome Trust (065061/Z). G.H.K.'s work on centromeres is supported by the National Institutes of Health (R01 GM066272).
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Glossary
- Kinetochore
-
Large structure composed of inner and outer regions that contain >80 proteins, which are required for spindle attachment, chromosome movement and regulation of the mitotic checkpoint.
- Aneuploidy
-
Gain or loss of chromosomes, associated with cell and organismal inviability, cancer and birth defects.
- Nucleosome
-
The basic unit of chromatin, containing DNA wrapped around a histone octamer.
- Syncytial cells
-
Cells that contain multiple nuclei, such as preblastoderm Drosophila embryos.
- RNA interference
-
(RNAi). Cellular mechanism involved in gene silencing and 'protection' from retroviral and transposable element invasion. Regulated by proteins such as Dicer and Argonaute, which are responsible for the production of siRNAs that target mRNAs for cleavage and that localize silencing factors to heterochromatic regions.
- Dicer
-
An RNA endonuclease which cleaves double-stranded RNA into siRNAs of approximately 21 bp.
- Argonaute
-
Double-stranded siRNAs are loaded into the Argonaute enzyme; conversion of a double-stranded to a single-stranded siRNA results in activation of the Argonaute. The resident siRNA guides the Argonaute protein to a homologous RNA molecule, allowing the protein to cleave the RNA in the annealed region.
- Heterochromatin protein 1
-
(HP1). Conserved component of silent heterochromatic regions, which contains a chromodomain that binds nucleosomes containing histone H3 that is methylated on lysine 9.
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Allshire, R., Karpen, G. Epigenetic regulation of centromeric chromatin: old dogs, new tricks?. Nat Rev Genet 9, 923–937 (2008). https://doi.org/10.1038/nrg2466
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DOI: https://doi.org/10.1038/nrg2466
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