Centromeric Sequences and Sequence Structures

Abstract

Centromere function is essential for the faithful passing on of the parental genome to daughter cells in cell division. This function is carried by specialised noncoding deoxyribonucleic acid (DNA), centromere DNA. The functional DNA element in human centromeres is the α‐satellite DNA, which we share with all other primates, but not with nonprimate species. This DNA acts through timed interactions with proteins belonging to the cell‐cycle machinery, such as topoisomerase II, which cuts the interconnecting bridges between sister‐chromatids to allow and enable the completion of mitotic and second state meiotic cell divisions. To orchestrate these interactions, centromere DNA has the ability to fold into complex three‐dimensional shapes, which are the form of the DNA recognised by its protein partners.

Key Concepts:

  • Unlike genes coding for proteins, noncoding DNA is not coded in a triplet code where each triplet can be translated into a specific amino acid.

  • Noncoding DNA is instead coded in the form of spatial structures capable of governing specific interactions with DNA, RNA and proteins in ways that are more reminiscent of antigen–antibody reactions than of the triplet coding.

  • For this reason scientists have had a hard time understanding what noncoding DNA is good for, at some point even leading to the misconception that it served no good function, but merely was ‘selfish DNA’.

  • With the discovery of the noncoding RNAs, which are very important for gene regulation, a very different picture is now dawning, and we trust that it will end in the understanding that genes are nothing more than ‘stupid’ data files, whereas the rest of the genome is ‘the software’ reading those data files to produce ‘the hardware’ in the form of gene products.

  • Centromere DNA is one species of noncoding DNA. It serves its functions through interactions with a whole range of DNA‐binding proteins, and to enable the interactions to be ‘on’ or ‘off’ as appropriate, the DNA must be able to turn into different shapes and forms, which are recognised, or not recognised by the various proteins.

Keywords: α‐satellite DNA; centromere DNA; centromere function; topoisomerase II

Figure 1.

α‐Satellite DNA is arranged in higher‐order tandem repeats. The organisation can be revealed by digestion with a restriction enzyme (R) that cuts the DNA once per higher‐order repeat (a). Each higher‐order repeat contains a number of 171 base pair (bp) monomers that can be revealed by digestion with the restriction enzyme DdeI, which cuts once within each monomer (b). The monomer itself consists of a conserved domain of 54 bp and a variable domain of 117 bp. The DdeI site is located in the conserved domain (c, d). The conserved domain contains two dyad symmetry elements divided by a (GT)2 element (e). The left symmetry (symmetry 1) has a centre (O), an inner and an outer element (IS and OS) and on one side IS and OS are separated by a hinge base (H). IS and OS elements are either homopurine or homopyrimidine. The DdeI site is found at the centre of the symmetry. The right symmetry (symmetry 2) has only one element on either side of the centre (O). Similar symmetry elements are found in centromere DNA from budding yeast, where the symmetry 1 homolog CDEIII is indispensable for mitotic function, and the symmetry 2 homolog CDEI is indispensable for meiotic function. Symmetry 1 forms a hairpin in vitro (f), which is cleaved by topoisomerase II at the site indicated by the arrow. The activity is critically dependent upon the orientation of the hinge base, as moving that base to the other side of the symmetry eliminates topo II activity.

Figure 2.

Two hairpins of the size shown in Figure fits inside one molecule of topo II (blue), when placed head to head. This positioning of the DNA inside the enzyme also places the observed cleavage site in the DNA opposite the catalytically active site of the enzyme, explaining why the DNA is cut in exactly that position.

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Further Reading

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West KL and Austin CA (1999) Human topoisomerase II binds and cleaves four‐way junction DNA in vitro. Nucleic Acids Research 27: 984–992.

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Koch, Jørn, and Andersen, Anni(Oct 2011) Centromeric Sequences and Sequence Structures. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005063.pub2]