Heterochromatin boundaries are hotspots for de novo kinetochore formation

Olszak, Agata; Essen, Dominic van; Pereira, António J.; Diehl, Sarah; Manke, Thomas; Maiato, Hélder; Saccani, Simona; Heun, Patrick

doi:10.1038/ncb2272

Cited by 116 publications

(124 citation statements)

References 62 publications

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“…In this study, we provide evidence that, in vegetative cells, ectopic CENP-A cnp1 preferentially assembles at the nuclear periphery, especially near heterochromatin. This is consistent with previous findings in Drosophila and fission yeast (Olszak et al 2011;Castillo et al 2013). Importantly, we provide the first evidence that ectopic CENP-A cnp1 chromatin also preferentially assembles near heterochromatin in meiotic cells.…”

supporting

confidence: 81%

“…A key attribute of an epigenetic mark is its heritability. In Drosophila, ectopically assembled CID induced by its overexpression can self-propagate through the cell cycle (Olszak et al 2011). Here, we provide the first evidence for a similar phenomenon in fission yeast.…”

supporting

confidence: 49%

“…In addition, CENP-A is overexpressed in many cancer cells, and this results in the incorporation of CENP-A at noncentromeric loci (Tomonaga et al 2003;Li et al 2007;Amato et al 2009;Scott and Sullivan 2014). In Drosophila, overexpression of the CENP-A homolog, CID, can lead to ectopic formation of heritable functional kinetochores and significant chromosome missegregation (Heun Olszak et al 2011). In budding yeast and Drosophila, ubiquitin-mediated proteolysis of CENP-A has been shown to contribute to the removal of mislocalized CENP-A at noncentromeric regions (Collins et al 2004;Moreno-Moreno et al 2006;Hewawasam et al 2010;Ranjitkar et al 2010).…”

mentioning

confidence: 99%

“…To determine whether ectopic CENP-A cnp1 -GFP chromatin overlaps with heterochromatin, we overexpressed CENP-A cnp1 -GFP at the intermediate level in a strain expressing mCherry-Swi6 at the endogenous level. We found a substantial overlap between CENP-A cnp1 -GFP and mCherry-Swi6 signals ( Figure 1D), indicating that ectopic CENP-A cnp1 -GFP chromatin can assemble near or within heterochromatin at the nuclear periphery.In Drosophila, the CENP-A homolog CID preferentially assembles at heterochromatin boundaries when it is overexpressed (Olszak et al 2011) …”

mentioning

confidence: 99%

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Ectopic Centromere Nucleation by CENP-A in Fission Yeast

González

Dong

et al. 2014

Genetics

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The centromere is a specific chromosomal locus that organizes the assembly of the kinetochore. It plays a fundamental role in accurate chromosome segregation. In most eukaryotic organisms, each chromosome contains a single centromere the position and function of which are epigenetically specified. Occasionally, centromeres form at ectopic loci, which can be detrimental to the cell. However, the mechanisms that protect the cell against ectopic centromeres (neocentromeres) remain poorly understood. Centromere protein-A (CENP-A), a centromere-specific histone 3 (H3) variant, is found in all centromeres and is indispensable for centromere function. Here we report that the overexpression of CENP-A Cnp1 in fission yeast results in the assembly of CENP-A Cnp1 at noncentromeric chromatin during mitosis and meiosis. The noncentromeric CENP-A preferentially assembles near heterochromatin and is capable of recruiting kinetochore components. Consistent with this, cells overexpressing CENP-A Cnp1 exhibit severe chromosome missegregation and spindle microtubule disorganization. In addition, pulse induction of CENP-A Cnp1 overexpression reveals that ectopic CENP-A chromatin can persist for multiple generations. Intriguingly, ectopic assembly of CENP-A cnp1 is suppressed by overexpression of histone H3 or H4. Finally, we demonstrate that deletion of the N-terminal domain of CENP-A cnp1 results in an increase in the number of ectopic CENP-A sites and provide evidence that the N-terminal domain of CENP-A prevents CENP-A assembly at ectopic loci via the ubiquitindependent proteolysis. These studies expand our current understanding of how noncentromeric chromatin is protected from mistakenly assembling CENP-A.T HE centromere is a specific chromosomal locus that organizes the assembly of the kinetochore. It is vital for the proper segregation of chromosomes during mitosis and meiosis (Allshire and Karpen 2008;Henikoff and Furuyama 2010). Most eukaryotic chromosomes contain a single centromere that is faithfully inherited at the same position within the chromosome through generations. In "point" centromeres of Saccharomyces cerevisiae, a specific 125-bp DNA sequence is both necessary and sufficient to specify centromere position (Clarke and Carbon 1980;Cottarel et al. 1989). However, most other eukaryotes contain regional centromeres, which are more complex and usually consist of large blocks of repetitive DNA sequences (Pluta et al. 1995;Henikoff et al. 2001). Epigenetic mechanisms appear to play a dominant role in the formation and inheritance of regional centromeres (Allshire and Karpen 2008;Henikoff and Furuyama 2010).Centromere protein-A (CENP-A), a centromere-specific histone 3 (H3) variant, has been proposed to act as the epigenetic mark for centromere positioning (Palmer et al. 1991;Henikoff and Furuyama 2010;Burrack and Berman 2012;Muller and Almouzni 2014). CENP-A partially replaces canonical histone H3 at the centromere and provides the structural and functional foundation for the assembly of the kinetochore (Blac...

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supporting

confidence: 81%

supporting

confidence: 49%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Ectopic Centromere Nucleation by CENP-A in Fission Yeast

González

Dong

et al. 2014

Genetics

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“…Interestingly, in Drosophila, centromere formation can be driven by overexpression of CENP-A. These ectopic centromeres also have the propensity to form adjacent to heterochromatin domains, suggesting a role for heterochromatin in neocentromere formation (Olszak et al 2011). However, such a role does not appear to be universally required for centromere formation as at least a subset of human neocentromeres appear to lack appreciable heterochromatin (Alonso et al 2010).…”

Section: The Role Of Dna Sequence In Centromere Specificationmentioning

confidence: 99%

Temporal control of epigenetic centromere specification

2012

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All living organisms require accurate mechanisms to faithfully inherit their genetic material during cell division. The centromere is a unique locus on each chromosome that supports a multiprotein structure called the kinetochore. During mitosis, the kinetochore is responsible for connecting chromosomes to spindle microtubules, allowing faithful segregation of the duplicated genome. In most organisms, centromere position and function is not defined by the local DNA sequence context but rather by an epigenetic chromatinbased mechanism. Centromere protein A (CENP-A) is central to this process, as chromatin assembled from this histone H3 variant is essential for assembly of the centromere complex, as well as for its epigenetic maintenance. As a major determinant of centromere function, CENP-A assembly requires tight control, both in its specificity for the centromere and in timing of assembly. In the last few years, there have been several new insights into the molecular mechanism that allow this process to occur. We will review these here and discuss the general implications of the mechanism of cell cycle coupling of centromere inheritance.

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Is the Heterochromatin of Meiotic Neocentromeres a Remnant of the Early Evolution of the Primitive Centromere?

Puertas

Villasanté

2013

Plant Centromere Biology

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Heterochromatin boundaries are hotspots for de novo kinetochore formation

Cited by 116 publications

References 62 publications

Ectopic Centromere Nucleation by CENP-A in Fission Yeast

Ectopic Centromere Nucleation by CENP-A in Fission Yeast

Temporal control of epigenetic centromere specification

Is the Heterochromatin of Meiotic Neocentromeres a Remnant of the Early Evolution of the Primitive Centromere?

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