In this diagram of a duplicated chromosome, (2) identifies the centromere—the region that joins the two sister chromatids, or each half of the chromosome. In prophase of mitosis, specialized regions on centromeres called kinetochores attach chromosomes to spindle fibers.
The centromere is the specialized DNA sequence of a chromosome that links a pair of sister chromatids (a dyad). During mitosis, spindle fibers attach to the centromere via the kinetochore. Centromeres were first thought to be genetic loci that direct the behavior of chromosomes.
The physical role of the centromere is to act as the site of assembly of the kinetochores – a highly complex multiprotein structure that is responsible for the actual events of chromosome segregation – i.e. binding microtubules and signalling to the cell cycle machinery when all chromosomes have adopted correct attachments to the spindle, so that it is safe for cell division to proceed to completion and for cells to enter anaphase.
There are, broadly speaking, two types of centromeres. "Point centromeres" bind to specific proteins that recognize particular DNA sequences with high efficiency.
Any piece of DNA with the point centromere DNA sequence on it will
typically form a centromere if present in the appropriate species. The
best characterised point centromeres are those of the budding yeast, Saccharomyces cerevisiae.
"Regional centromeres" is the term coined to describe most centromeres,
which typically form on regions of preferred DNA sequence, but which
can form on other DNA sequences as well. The signal for formation of a regional centromere appears to be epigenetic. Most organisms, ranging from the fission yeast Schizosaccharomyces pombe to humans, have regional centromeres.
Regarding mitotic chromosome structure, centromeres represent a
constricted region of the chromosome (often referred to as the primary
constriction) where two identical sister chromatids
are most closely in contact. When cells enter mitosis, the sister
chromatids (the two copies of each chromosomal DNA molecule resulting
from DNA replication in chromatin form) are linked along their length by the action of the cohesin
complex. It is now believed that this complex is mostly released from
chromosome arms during prophase, so that by the time the chromosomes
line up at the mid-plane of the mitotic spindle (also known as the
metaphase plate), the last place where they are linked with one another
is in the chromatin in and around the centromere.
Position
Classifications of Chromosomes
A: Short arm (p arm)
B: Centromere
C: Long arm (q arm)
D: Sister Chromatids
| 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. |
B: Centromere
C: Long arm (q arm)
D: Sister Chromatids
Each chromosome has two arms, labeled p (the shorter of the two) and q
(the longer). Many remember that the short arm 'p' is named for the
French word "petit" meaning 'small', although this explanation was shown
to be apocryphal. They can be connected in either metacentric, submetacentric, acrocentric or telocentric manner.
| Categorization of chromosomes according to the relative arms length | ||||||
| Centromere position | Arms length ratio | Sign | Description | |||
| Medial sensu stricto | 1.0 – 1.6 | M | Metacentric | |||
| Medial region | 1.7 | m | Metacentric | |||
| Submedial | 3.0 | sm | Submetacentric | |||
| Subterminal | 3.1 – 6.9 | st | Subtelocentric | |||
| Terminal region | 7.0 | t | Acrocentric | |||
| Terminal sensu stricto | ∞ | T | Telocentric | |||
| Notes | – | Metacentric: M+m | Atelocentric: M+m+sm+st+t | |||
Metacentric
These are X-shaped chromosomes, with the centromere in the middle so that the two arms of the chromosomes are almost equal.
A chromosome is metacentric if its two arms are roughly equal in length. In a normal human karyotype,
five chromosomes are considered metacentric: chromosomes 1, 3, 16, 19,
and 20. In some cases, a metacentric chromosome is formed by balanced
translocation: the fusion of two acrocentric chromosomes to form one metacentric chromosome.
Submetacentric
If the arms' lengths are unequal, the chromosome is said to be submetacentric. They are L-shaped.
Acrocentric
If the p (short) arm is so short that it is hard to observe, but still present, then the chromosome is acrocentric (the "acro-" in acrocentric refers to the Greek word for "peak"). The human genome includes five acrocentric chromosomes: 13, 14, 15, 21, 22. The Y chromosome is also acrocentric.
In an acrocentric chromosome the p arm contains genetic material
including repeated sequences such as nucleolar organizing regions, and
can be translocated without significant harm, as in a balanced Robertsonian translocation. The domestic horse genome includes one metacentric chromosome that is homologous to two acrocentric chromosomes in the conspecific but undomesticated Przewalski's horse.
This may reflect either fixation of a balanced Robertsonian
translocation in domestic horses or, conversely, fixation of the fission
of one metacentric chromosome into two acrocentric chromosomes in
Przewalski's horses. A similar situation exists between the human and
great ape genomes, with a reduction of two acrocentric chromosomes in
the great apes to one metacentric chromosome in humans (see aneuploidy and the human chromosome 2).
Strikingly, harmful translocations in disease context, especially
unbalanced translocations in blood cancers, more frequently involve
acrocentric chromosomes than non-acrocentric chromosomes. Although the cause is not known, this probably relates to the physical location of acrocentric chromosomes within the nucleus. Acrocentric chromosomes are usually located in and around the nucleolus, so in the center of the nucleus, where chromosomes tend to be less densely packed than chromosomes in the nuclear periphery. Consistently, chromosomal regions that are less densely packed are also more prone to chromosomal translocations in cancers.
Telocentric
A
telocentric chromosome's centromere is located at the terminal end of
the chromosome. A telocentric chromosome has therefore only one arm. Telomeres may extend from both ends of the chromosome, their shape is similar to letter "i" during anaphase. For example, the standard house mouse karyotype has only telocentric chromosomes. Humans do not possess telocentric chromosomes.
Subtelocentric
If the chromosome's centromere is located closer to its end than to its center, it may be described as subtelocentric.
Centromere number
Acentric
If a chromosome lacks a centromere, it is said acentric. The macronucleus of ciliates for example contains hundreds of acentric chromosomes. Chromosome-breaking events can also generate acentric chromosomes or acentric fragments.
Dicentric
A dicentric chromosome
is an abnormal chromosome with two centromeres. It is formed through
the fusion of two chromosome segments, each with a centromere, resulting
in the loss of acentric fragments (lacking a centromere) and the
formation of dicentric fragments. The formation of dicentric chromosomes has been attributed to genetic processes, such as Robertsonian translocation and paracentric inversion.
Dicentric chromosomes have important roles in the mitotic stability of
chromosomes and the formation of pseudodicentric chromosomes.
Monocentric
The monocentric chromosome is a chromosome that has only one centromere in a chromosome and forms a narrow constriction.
Monocentric centromeres are the most common structure on highly repetitive DNA in plants and animals.
Holocentric
Different
than monocentric chromosones in holocentric chromosomes, the entire
length of the chromosome acts as the centromere. In holocentric
chromosomes there is not one primary constriction but the centromere has
many CenH3 loci spread over the whole chromosome. Examples of this type of centromere can be found scattered throughout the plant and animal kingdoms, with the most well-known example being the nematode Caenorhabditis elegans.
Polycentric
Human chromosomes
| Chromosome | Centromere position (Mbp) |
Category | Chromosome Size (Mbp) |
Centromere size (Mbp) |
|---|---|---|---|---|
| 1 | 125.0 | metacentric | 247.2 | 7.4 |
| 2 | 93.3 | submetacentric | 242.8 | 6.3 |
| 3 | 91.0 | metacentric | 199.4 | 6.0 |
| 4 | 50.4 | submetacentric | 191.3 | — |
| 5 | 48.4 | submetacentric | 180.8 | — |
| 6 | 61.0 | submetacentric | 170.9 | — |
| 7 | 59.9 | submetacentric | 158.8 | — |
| 8 | 45.6 | submetacentric | 146.3 | — |
| 9 | 49.0 | submetacentric | 140.4 | — |
| 10 | 40.2 | submetacentric | 135.4 | — |
| 11 | 53.7 | submetacentric | 134.5 | — |
| 12 | 35.8 | submetacentric | 132.3 | — |
| 13 | 17.9 | acrocentric | 114.1 | — |
| 14 | 17.6 | acrocentric | 106.3 | — |
| 15 | 19.0 | acrocentric | 100.3 | — |
| 16 | 36.6 | metacentric | 88.8 | — |
| 17 | 24.0 | submetacentric | 78.7 | — |
| 18 | 17.2 | submetacentric | 76.1 | — |
| 19 | 26.5 | metacentric | 63.8 | — |
| 20 | 27.5 | metacentric | 62.4 | — |
| 21 | 13.2 | acrocentric | 46.9 | — |
| 22 | 14.7 | acrocentric | 49.5 | — |
| X | 60.6 | submetacentric | 154.9 | — |
| Y | 12.5 | acrocentric | 57.7 | — |
Sequence
There are two types of centromeres.[27] 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.[28]
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.[28]
Inheritance
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.[29]
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.[30]
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.
Structure
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.[31]
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[32]
which are known heterochromatic modifications. In Drosophila, Islands
of retroelements are major components of the centromeres. [33]
In the yeast Schizosaccharomyces pombe (and probably in other eukaryotes), the formation of centromeric heterochromatin is connected to RNAi.[34] 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.
Centromeric aberrations
In rare cases in humans, neocentromeres
can form at new sites on the chromosome. There are currently over 90
known human neocentromeres identified on 20 different chromosomes.[35][36]
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.
Centromere proteins are also the autoantigenic target for some anti-nuclear antibodies, such as anti-centromere antibodies.
Dysfunction and disease
It
has been known that centromere misregulation contributes to
mis-segregation of chromosomes, which is strongly related to cancer and
abortion. Notably, overexpression of many centromere genes have been
linked to cancer malignant phenotypes. Overexpression of these
centromere genes can increase genomic instability in cancers.[37]
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.[38] Instability of centromere repetitive DNA was recently shown in cancer and aging.[39]
Etymology and pronunciation
The word centromere (/ˈsɛntrəˌmɪər/[40][41]) uses combining forms of centro- and -mere, yielding "central part", describing the centromere's location at the center of the chromosome.
