Centromere

Classifications of Chromosomes

I	Telocentric	Centromere placement very close to the top, p arms barely visible if visible at all.
II	Acrocentric	q arms are still much longer than the p arms, but the p arms are longer than those in telocentric.
III	Submetacentric	p and q arms are very close in length but not equal.
IV	Metacentric	p and q arms are equal in length.

A: Short arm (p arm)
B: Centromere
C: Long arm (q arm)
D: Sister Chromatids

In humans, centromere positions define the chromosomal karyotype, in which each chromosome has two arms, p (the shorter of the two) and q (the longer). The short arm 'p' is reportedly named for the French word "petit" meaning 'small'.[1] The position of the centromere relative to any particular linear chromosome is used to classify chromosomes as metacentric, submetacentric, acrocentric, telocentric, or holocentric.[2][3]

There are two types of centromeres.[16] In regional centromeres, DNA sequences contribute to but do not define function. Regional centromeres contain large amounts of DNA and are often packaged into heterochromatin. In most eukaryotes, the centromere's DNA sequence consists of large arrays of repetitive DNA (e.g. satellite DNA) where the sequence within individual repeat elements is similar but not identical. In humans, the primary centromeric repeat unit is called α-satellite (or alphoid), although a number of other sequence types are found in this region.[17] Centromere satellites evolve rapidly between species, and analyses in wild mice show that satellite copy number and heterogeneity relates to population origins and subspecies.[18] Additionally, satellite sequences may be affected by inbreeding.[18]

Point centromeres are smaller and more compact. DNA sequences are both necessary and sufficient to specify centromere identity and function in organisms with point centromeres. In budding yeasts, the centromere region is relatively small (about 125 bp DNA) and contains two highly conserved DNA sequences that serve as binding sites for essential kinetochore proteins.[17]

Since centromeric DNA sequence is not the key determinant of centromeric identity in metazoans, it is thought that epigenetic inheritance plays a major role in specifying the centromere.[19] The daughter chromosomes will assemble centromeres in the same place as the parent chromosome, independent of sequence. It has been proposed that histone H3 variant CENP-A (Centromere Protein A) is the epigenetic mark of the centromere.[20] The question arises whether there must be still some original way in which the centromere is specified, even if it is subsequently propagated epigenetically. If the centromere is inherited epigenetically from one generation to the next, the problem is pushed back to the origin of the first metazoans.

The centromeric DNA is normally in a heterochromatin state, which is essential for the recruitment of the cohesin complex that mediates sister chromatid cohesion after DNA replication as well as coordinating sister chromatid separation during anaphase. In this chromatin, the normal histone H3 is replaced with a centromere-specific variant, CENP-A in humans.[21] The presence of CENP-A is believed to be important for the assembly of the kinetochore on the centromere. CENP-C has been shown to localise almost exclusively to these regions of CENP-A associated chromatin. In human cells, the histones are found to be most enriched for H4K20me3 and H3K9me3[22] which are known heterochromatic modifications. In Drosophila, Islands of retroelements are major components of the centromeres.[23]

In the yeast Schizosaccharomyces pombe (and probably in other eukaryotes), the formation of centromeric heterochromatin is connected to RNAi.[24] In nematodes such as Caenorhabditis elegans, some plants, and the insect orders Lepidoptera and Hemiptera, chromosomes are "holocentric", indicating that there is not a primary site of microtubule attachments or a primary constriction, and a "diffuse" kinetochore assembles along the entire length of the chromosome.

In rare cases, neocentromeres can form at new sites on a chromosome as a result of a repositioning of the centromere. This phenomenon is most well known from human clinical studies and there are currently over 90 known human neocentromeres identified on 20 different chromosomes.[25][26] The formation of a neocentromere must be coupled with the inactivation of the previous centromere, since chromosomes with two functional centromeres (Dicentric chromosome) will result in chromosome breakage during mitosis. In some unusual cases human neocentromeres have been observed to form spontaneously on fragmented chromosomes. Some of these new positions were originally euchromatic and lack alpha satellite DNA altogether. Neocentromeres lack the repetitive structure seen in normal centromeres which suggest that centromere formation is mainly controlled epigenetically.[27][28] Over time a neocentromere can accumulate repetitive elements and mature into what is known as an evolutionary new centromere. There are several well known examples in primate chromosomes where the centromere position is different from the human centromere of the same chromosome and is thought to be evolutionary new centromeres.[27] Centromere repositioning and the formation of evolutionary new centromeres has been suggested to be a mechanism of speciation.[29]

Centromere proteins are also the autoantigenic target for some anti-nuclear antibodies, such as anti-centromere antibodies.

It has been known that centromere misregulation contributes to mis-segregation of chromosomes, which is strongly related to cancer and miscarriage. Notably, overexpression of many centromere genes have been linked to cancer malignant phenotypes. Overexpression of these centromere genes can increase genomic instability in cancers. Elevated genomic instability on one hand relates to malignant phenotypes; on the other hand, it makes the tumor cells more vulnerable to specific adjuvant therapies such as certain chemotherapies and radiotherapy.[30] Instability of centromere repetitive DNA was recently shown in cancer and aging.[31]

When DNA breaks occur at centromeres in the G1 phase of the cell cycle, the cells are able to recruit the homologous recombinational repair machinery to the damaged site, even in the absence of a sister chromatid.[32] It appears that homologous recombinational repair can occur at centromeric breaks throughout the cell cycle in order to prevent the activation of inaccurate mutagenic DNA repair pathways and to preserve centromeric integrity.[32]

The word centromere (/ˈsɛntrəˌmɪər/[33][34]) uses combining forms of centro- and -mere, yielding "central part", describing the centromere's location at the center of the chromosome.

• Telomere
• Chromatid
• Diploid
• Monopolin

• "Rice Centromere, Supposedly Quiet Genetic Domain, Surprises". ScienceDaily (Press release). January 13, 2004.

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