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Chromosomes undergo major changes in structure and organization during the cell cycle (FIG.1). They condense during mitosis, and during this stage, as first described by Walther Flemming in 1882 (REF.1), human centro meres become visible as chromosomal constrictions. The specialized nature and environment of centromeric chromatin enables the assembly of the kinetochore, which is a large, multi-protein complex that attaches to micro-tubules during cell division (for reviews, see REFS2,3),
thereby ensuring equal partitioning of genetic material between daughter cells. Following each cell division, chromatin decondenses, the structure and biochemical composition of centromeres change, andkinetochores disassemble. During mitosis, this decompaction is visualized by weak DNA staining on individual chromosomes (FIG.1). In interphase, specialized densely stained chromocentres become visible in mouse cells. They correspond to pericentric heterochromatin (PHC) bringing several chromosomes together.
The smallest characterized centromere to date is the point centromere in Saccharomyces cerevisiae, which captures one spindle microtubule4 and measures 125 bp of DNA of a unique sequence dictating centro-mere location (BOX1). At the other extreme, species such as Caenorhabditis elegans have evolved holocentromeres, in which microtubule attachment sites extend along large portions of the chromosome5. These holocentromeres are considered to be point centromeres that are dispersed across the entire chromosome6.
This shows the high plasticity of the organization of centro meres across different organisms (BOX1) and the
existence of various means to segregate chromosomes. Regional centromeres, which are found in most other eukaryotes, can span up to several mega base pairs (Mb) and attach to several microtubules7. In most eukaryotes, they are found at repetitive DNA sequences, known as
-satellite sequences in humans8. These repeats vary in length and sequence between species9. In species with regional centromeres, a single centromere is normally active on each chromosome: if two centromeres occur on a chromosome, this leads to aberrant segregation. The mammalian X and Y chromosomes harbour repetitive sequences that differ from those of the other chromosomes10, and under rare circumstances these repetitive sequences can form centromeres at ectopic sites. The existence of neocentromeres at sequences that lack the typical centromeric repeats11 led to the hypothesis that epigenetic features could determine centromere location.
Most eukaryotic centromeres are marked by the histone H3 variant centromere protein A (CENP-A)12.
Earnshaw and...