Centromeres

Abstract

Cell division requires the faithful partitioning of the replicated genome into two daughter cells. Failure to achieve this can result in cell death or drive neoplastic transformation and, in meiosis, can lead to infertility and aneuploidy. Centromeres are sites at which eukaryotic chromosomes interact with the mitotic spindle and sister chromatids remain linked until properly aligned. Linkage to the spindle occurs via the kinetochore – a highly elaborate proteinaceous structure assembled on the surface of the centromere. Paradoxically given their essential functions, there is a surprising diversity in centromeric architecture, deoxyribonucleic acid (DNA) sequence and protein composition across eukaryotes. Centromere assembly and maintenance are epigenetically determined, and their key unifying feature is the presence of a centromere‐specific histone H3 variant: CENP‐A. In this article, the authors have focused on the specification, composition and function of the mammalian centromere in mitosis.

Key Concepts:

  • Centromeres are chromosomal loci necessary for chromosome segregation.

  • The most common form of centromere is the regional centromere that is present once, and only once, per chromosome.

  • Centromeres are epigenetically regulated; the centromere‐specific histone H3 variant CENP‐A is the determinant of centromere identity.

  • Centromeres assemble kinetochores consisting of multiple copies of >100 proteins that regulate chromosome interactions with the mitotic spindle.

  • Centromeres are flanked by heterochromatin, which is necessary for sister chromatid cohesion and error correction.

  • Plasticity in centromere positioning and activity can compensate for the loss or gain of a centromere on a single chromosome fragment.

Keywords: centromere; CENP‐A; chromatin; chromosomes; epigenetics; kinetochore; mitosis

Figure 1.

Features of centromeric and pericentromeric chromatin. Regional centromeres form over a chromosome's primary constriction and are marked by the presence of the H3‐variant CENP‐A (red). H3‐containing nucleosomes (orange) in the centromeric domain show post‐translational modifications typical of transcribed regions of the genome. The centromere acts as a binding site for the CCAN, which, in turn, serves as a scaffold for the formation of the kinetochore and proteins that help to propagate the centromeric state. The pericentromere flanking the centromere is a heterochromatic region marked by numerous features of constitutive heterochromatin: methylated CpG dinucleotides, HP1 proteins and characteristic post‐translational histone modifications. Sister chromatids are linked until anaphase onset via this region thanks to the retention of cohesin through the action of shugoshin.

Figure 2.

The constitutive centromere associated network. The centromere acts as a platform for kinetochore assembly. CCAN members (blue) interact with CENP‐A (red), DNA or one other to form a proteinaceous network. The CCAN recruits the KMN network (brown) that anchors microtubules (green) to the kinetochore. The CPC localises to the inner centromere and generates a gradient of Aurora B kinase activity (purple) necessary for tension sensing and promoting the attachment of sister chromatids to opposite poles. H3‐containing nucleosomes are shown in orange.

Figure 3.

Models of 3‐D centromere architecture Centromeric regions contain interspersed domains of CENP‐A and H3‐containing nucleosomes, the latter of which contain histone modifications typical of transcribed regions (chromatin fibre micrograph by Jan Bergmann). Two models have been put forward for the 3‐D organisation of centromeric chromatin. (A) The ‘amphipathic’ solenoid model postulates that CENP‐A‐containing domains (red) face the exterior and H3‐containing domains (orange) the interior of the centromere. The kinetochore (blue) to which microtubules (green) can attach forms on the outer face of the centromere. (B) The boustrophedon model proposes that discrete CENP‐A and H3 domains are folded in a sinusoidal manner to form a two‐dimensional plate called a boustrophedon. Several such plates are stacked on top of one other to form the centromeric foundation for the kinetochore to which microtubules can attach.

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Further Reading

Buscaino A, Allshire R and Pidoux A (2010) Building centromeres: home sweet home or a nomadic existence? Current Opinion in Genetics and Development 20(2): 118–126.

Earnshaw WCE, Allshire RC, Black BE et al. (2013) Esperanto for histones: CENP‐A, not CenH3, is the centromeric histone H3 variant. Chromosome Research 21(2): 101–106.

Maiato H, DeLuca J, Salmon ED and Earnshaw WC (2004) The dynamic kinetochore‐microtubule interface. Journal of Cell Science 117(Pt23): 5461–5477.

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Schueler MG and Sullivan BA (2006) Structural and functional dynamics of human centromeric chromatin. Annual Review of Genomics and Human Genetics 7:301–313.

Stimpson KM, Matheny JE and Sullivan BA (2012) Dicentric chromosomes: unique models to study centromere function and inactivation. Chromosome Research 20(5): 595–605.

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Gohard, Florence H, Zhiteneva, Alisa A, and Earnshaw, William C(Mar 2014) Centromeres. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005785.pub2]