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Determining centromere identity: cyclical stories and forking paths

Nature Reviews Genetics volume 2, pages 584–596 (2001)Cite this article

Abstract

The centromere is the genetic locus required for chromosome segregation. It is the site of spindle attachment to the chromosomes and is crucial for the transfer of genetic information between cell and organismal generations. Although the centromere was first recognized more than 120 years ago, little is known about what determines its site(s) of activity, and how it contributes to kinetochore formation and spindle attachment. Recent work in this field has supported the hypothesis that most eukaryotic centromeres are determined epigenetically rather than by primary DNA sequence. Here, we review recent studies that have elucidated the organization and functions of centromeric chromatin, and evaluate present-day models for how centromere identity and propagation are determined.

Key Points

  • Eukaryotic centromeres are encoded by non-conserved DNAs but contain highly conserved proteins, such as CENPA. Furthermore, centromeric DNAs that lack centromere function and non-centromeric DNAs can gain centromere function. Despite a lack of conservation in centromeric DNA sequence, (A+T)-rich or repetitive DNA might be a primary substrate for kinetochore assembly.

  • CENPA is an essential kinetochore histone that might epigenetically mark sites for kinetochore formation and is required for the proper localization of kinetochore and sister-chromatid cohesion proteins. It is also required for mitotic and cell-cycle progression. Its incorporation into centromeres is independent of:

  • centromeric DNA replication, because replication studies of human and Drosophila centromeres indicate that centromeric DNAs are replicated asynchronously in S phase, and in humans are replicated before CENPA is loaded onto chromatin;

  • the spatial organization or sequestration of centromeres or replication domains.

  • Eukaryotic centromere regions are composed of several spatial and functional domains.

  • Epigenetic propagation of centromere identity might be achieved through the activity of centromere-specific chromatin-assembly factors, which load CENPA into centromeric nucleosomes.

  • Despite recent advances in our understanding of centromere function, many mechanistic details remain to be understood.

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Figure 1: Structural and functional elements of the centromere region.
Figure 2: Centromeric DNAs and conservation of CENPA at structurally distinct centromeres.
Figure 3: Structural and functional analyses of protein subdomains in the centromere region.
Figure 4: Models for the propagation of centromere identity.
Figure 5: A repeat-subunit and presentation model for centromeric chromatin in different species.

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Acknowledgements

We thank K. Sullivan for critical comments on the manuscript, and L. Moore and M. Roth (Fred Hutchison Cancer Research Center, Seattle) for the image in figure 2e. Our research on centromeres is supported by grants from the National Institutes of Health.

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  1. Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Beth A. Sullivan, Michael D. Blower & Gary H. Karpen

  2. Department of Biology, University of California at San Diego, La Jolla, 92037, California, USA

    Michael D. Blower

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BUB-1

MCAK

HCP-1

Polo

Cmet

Rod

Mei-S332

Cid

Swi6

Chp1

Mis6

Cnp1

mis12

Hp1

Prod

INCENP

Scc1

Cse4

ndc10

HCP-3

Clr4

Rik1

FURTHER INFORMATION

Walther Flemming

Barbara McClintock

Centromere research labs

Gary Karpen's lab

Glossary

ANEUPLOIDY

The presence of extra copies, or no copies, of some chromosomes.

CENTROMERE

The genetic locus required for chromosome segregation; contains DNA and proteins on which the kinetochore is formed.

PLATEWARD METAPHASE MOVEMENTS

(prometaphase congression). The movement of condensing chromosomes towards the metaphase plate, during which they capture spindle microtubules and orientate themselves in preparation for anaphase sister-chromatid separation.

POLEWARD ANAPHASE MOVEMENTS

The movement of chromatids along spindle microtubules towards the spindle poles.

CENTROMERE REGION

Chromatin and DNA in the vicinity of the functional centromere, including the pericentric heterochromatin.

HETEROCHROMATIN

A cytologically defined genomic component that contains repetitive DNA (highly repetitive satellite DNA, transposable elements and ribosomal DNA gene clusters) and some protein-coding genes. Most eukaryotic centromeres are embedded in heterochromatin.

SPINDLE ASSEMBLY CHECKPOINT (SAC).

A highly conserved surveillance mechanism in mitosis and meiosis that minimizes chromosome loss by preventing chromosomes from initiating anaphase until all kinetochores have successfully captured spindle microtubules.

MONOCENTRIC

When a kinetochore forms on a specific, limited region of a chromosome.

HOLOCENTRIC

When a kinetochore forms along the entire length of a chromosome.

DYNEINS

Microtubule-based molecular motors that move towards the minus end of microtubules.

KINESINS

Microtubule-based molecular motors that, in general, move towards the fast-growing, plus end of microtubules.

EPIGENETIC

Any heritable influence (in the progeny of cells or of individuals) on chromosome or gene function that is not accompanied by a change in DNA sequence. Examples of epigenetic events include mammalian X-chromosome inactivation, imprinting, centromere inactivation and position effect variegation.

POSITION EFFECT VARIEGATION (PEV).

The variable, heritable suppression of genes by their juxtaposition to heterochromatin or telomeres, or by movement of a gene into a different nuclear domain or chromosomal context.

MINICHROMOSOME

An extranumerary chromosome that contains functional elements, such as telomeres and centromeres, and is transmitted in meiosis and mitosis.

CENPA

A centromere-specific, histone H3-like protein.

CENPC

A constitutive kinetochore protein. Its localization to the inner kinetochore is dependent on CENPA.

CHP1

A Schizosaccharomyces pombe chromodomain protein.

HETEROCHROMATIN PROTEIN 1 (Hp1)

A Drosophila heterochromatin protein that contains chromodomains.

MEI-S332

A centromere-region protein involved in sister-chromatid cohesion.

MIS6

A centromere protein that binds to the central core of the Schizosaccharomyces pombe centromere and is required to establish or maintain centromeric chromatin structure.

SWI6

A chromodomain-containing Schizosaccharomyces pombe homologue of Drosophila heterochromatin protein 1. The chromodomain is a protein motif — common to proteins that in some cases interact with chromatin — that is involved in binding certain methylated histones; often associated with transcriptional repression.

SU(VAR)3-9

A chromatin-binding translation initiation factor that suppresses position effect variegation in flies. Mammalian and Schizosaccharomyces pombe Su(Var)3-9 homologues are present in the centromere region of mitotic chromosomes, and encode a histone H3 methyltransferase.

ANAPHASE BRIDGES

The physical stretching of dicentric chromosomes during anaphase due to the orientation and movement of linked kinetochores towards opposite spindle poles.

NEOCENTROMERE

Chromosomal sites that do not contain typical repetitive centromeric DNA but do acquire centromeric chromatin, can assemble kinetochores, can recruit other centromeric proteins, and are transmitted faithfully in meiosis and mitosis.

ACENTRIC

A chromosome or chromosomal fragment that lacks a centromere.

BOUNDARY ELEMENTS

Chromatin that acts as an insulator to block changes in chromatin structure, protein binding, or the spreading of functional domains.

HISTONE

A family of small, highly conserved basic proteins, found in the chromatin of all eukaryotic cells, that associate with DNA to form a nucleosome.

CREST ANTISERA

Autoantibodies that recognize centromeric antigens (CENPs) found in the sera of patients with autoimmune diseases, such as CREST (calcinosis, Raynaud syndrome, oesophageal dysmotility, scleroderma and telangiectasia).

NUCLEOSOME

The fundamental unit into which DNA and histones are packaged in eukaryotic cells.

RNA INTERFERENCE (RNAi)

A process by which double-stranded RNA specifically silences the expression of homologous genes by degrading their cognate mRNA.

CHROMATIN IMMUNOPRECIPITATION (ChIP)

A technique that isolates sequences from soluble DNA chromatin extracts (complexes of DNA and protein) using antibodies that recognize specific chromosomal proteins.

INNER CENTROMERE PROTEIN (Incenp)

A family of proteins that transiently localize to the region between sister-chromatid kinetochores during mitosis.

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Sullivan, B., Blower, M. & Karpen, G. Determining centromere identity: cyclical stories and forking paths. Nat Rev Genet 2, 584–596 (2001). https://doi.org/10.1038/35084512

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