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The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis,
spindle fibers In cell biology, the spindle apparatus refers to the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a pr ...
attach to the centromere via the
kinetochore A kinetochore (, ) is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and ...
. The physical role of the centromere is to act as the site of assembly of the
kinetochores A kinetochore (, ) is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and ...
– a highly complex multiprotein structure that is responsible for the actual events of chromosome segregation – i.e. binding
microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 a ...
and signaling to the cell cycle machinery when all chromosomes have adopted correct attachments to the spindle, so that it is safe for
cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...
to proceed to completion and for cells to enter
anaphase Anaphase () is the stage of mitosis after the process of metaphase, when replicated chromosomes are split and the newly-copied chromosomes (daughter chromatids) are moved to opposite poles of the cell. Chromosomes also reach their overall maxim ...
. There are, broadly speaking, two types of centromeres. "Point centromeres" bind to specific
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s that recognize particular DNA
sequences In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is called t ...
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 characterized point centromeres are those of the budding yeast, ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...
''. "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 ''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measur ...
'' 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 molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
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

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'. The position of the centromere relative to any particular linear chromosome is used to classify chromosomes as metacentric, submetacentric, acrocentric, telocentric, or holocentric.


Metacentric

Metacentric means that the centromere is positioned midway between the chromosome ends, resulting in the arms being approximately equal in length. When the centromeres are metacentric, the chromosomes appear to be "x-shaped."


Submetacentric

Submetacentric means that the centromere is positioned below the middle, with one chromosome arm shorter than the other, often resulting in an L shape.


Acrocentric

An acrocentric chromosome's centromere is situated so that one of the chromosome arms is much shorter than the other. The "acro-" in acrocentric refers to the Greek word for "peak." The
human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the ...
includes six acrocentric chromosomes. Five autosomal acrocentric chromosomes: 13, 14, 15, 21, 22; and the
Y chromosome The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abse ...
is also acrocentric. Short acrocentric p-arms contain little genetic material and can be translocated without significant harm, as in a balanced Robertsonian translocation. In addition to some protein coding genes, human acrocentric p-arms also contain
Nucleolus organizer region ] Nucleolus organizer regions (NORs) are chromosome, chromosomal regions crucial for the formation of the nucleolus. In humans, the NORs are located on the short arms of the acrocentric chromosomes 13, 14, 15, 21 and 22, the genes RNR1, RNR2, RNR ...
s (NORs), from which
ribosomal RNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosom ...
is transcribed. However, a proportion of acrocentric p-arms in cell lines and tissues from normal human donors do not contain detectable NORs. The
domestic horse The horse (''Equus ferus caballus'') is a Domestication, domesticated, odd-toed ungulate, one-toed, ungulate, hoofed mammal. It belongs to the taxonomic family Equidae and is one of two Extant taxon, extant subspecies of wild horse, ''Equus fer ...
genome includes one metacentric chromosome that is homologous to two acrocentric chromosomes in the
conspecific Biological specificity is the tendency of a characteristic such as a behavior or a biochemical variation to occur in a particular species. Biochemist Linus Pauling stated that "Biological specificity is the set of characteristics of living organis ...
but undomesticated
Przewalski's horse Przewalski's horse (, , (Пржевальский ), ) (''Equus ferus przewalskii'' or ''Equus przewalskii''), also called the takhi, Mongolian wild horse or Dzungarian horse, is a rare and endangered horse originally native to the steppes of ...
. 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 Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
and the human chromosome 2). Many diseases from the result of unbalanced translocations more frequently involve acrocentric chromosomes than other non-acrocentric chromosomes. Acrocentric chromosomes are usually located in and around the
nucleolus The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of ...
. As a result these 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

Telocentric chromosomes have a centromere at one end of the chromosome and therefore exhibit only one arm at the cytological (microscopic) level. They are not present in human but can form through cellular chromosomal errors. Telocentric chromosomes occur naturally in many species, such as the house mouse, in which all chromosomes except the Y are telocentric.


Subtelocentric

Subtelocentric chromosomes' centromeres are located between the middle and the end of the chromosomes, but reside closer to the end of the chromosomes.


Centromere types


Acentric

An acentric chromosome is fragment of a chromosome that lacks a centromere. Since centromeres are the attachment point for spindle fibers in cell division, acentric fragments are not evenly distributed to daughter cells during cell division. As a result, a daughter cell will lack the acentric fragment and deleterious consequences could occur. Chromosome-breaking events can also generate acentric chromosomes or acentric fragments.   


Dicentric

A
dicentric chromosome 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 dicent ...
is an abnormal chromosome with two centromeres, which can be unstable through cell divisions. It can form through translocation between or fusion of two chromosome segments, each with a centromere. Some rearrangements produce both dicentric chromosomes and acentric fragments which can not attach to spindles at mitosis. The formation of dicentric chromosomes has been attributed to genetic processes, such as Robertsonian translocation and paracentric inversion. Dicentric chromosomes can have a variety of fates, including mitotic stability. In some cases, their stability comes from inactivation of one of the two centromeres to make a functionally monocentric chromosome capable of normal transmission to daughter cells during cell divisio


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

Unlike monocentric chromosomes, holocentric chromosomes have no distinct primary constriction when viewed at mitosis. Instead, spindle fibers attach along almost the entire (Greek: holo-) length of the chromosome. In holocentric chromosomes centromeric proteins, such as CENPA (CenH3) are spread over the whole chromosome. The nematode, Caenorhabditis elegans, is a well-known example of an organism with holocentric chromosomes, but this type of centromere can be found in various species, plants, and animals, across eukaryotes. Holocentromeres are actually composed of multiple distributed centromere units that form a line-like structure along the chromosomes during mitosis. Alternative or nonconventional strategies are deployed at meiosis to achieve the homologous chromosome pairing and segregation needed to produce viable gametes or gametophytes for sexual reproduction. Different types of holocentromeres exist in different species, namely with or without centromeric repetitive DNA sequences and with or without CenH3. Holocentricity has evolved at least 13 times independently in various green algae, protozoans, invertebrates, and different plant families. Contrary to monocentric species where acentric fragments usually become lost during cell division, the breakage of holocentric chromosomes creates fragments with normal spindle fiber attachment sites. Because of this, organisms with holocentric chromosomes can more rapidly evolve karyotype variation, able to heal fragmented chromosomes through subsequent addition of telomere caps at the sites of breakage.


Polycentric


Human chromosomes

Based on the micrographic characteristics of size, position of the centromere and sometimes the presence of a chromosomal satellite, the human chromosomes are classified into the following groups:


Sequence

There are two types of centromeres. 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 Satellite DNA consists of very large arrays of tandemly repeating, non-coding DNA. Satellite DNA is the main component of functional centromeres, and form the main structural constituent of heterochromatin. The name "satellite DNA" refers to the ...
) 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. Centromere satellites evolve rapidly between species, and analyses in wild mice show that satellite copy number and heterogeneity relates to population origins and subspecies. Additionally, satellite sequences may be affected by inbreeding. 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 A kinetochore (, ) is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and ...
proteins.


Inheritance

Since centromeric DNA sequence is not the key determinant of centromeric identity in
metazoans Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...
, it is thought that epigenetic inheritance plays a major role in specifying the centromere. 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. 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 In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
H3 is replaced with a centromere-specific variant, CENP-A in humans. 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 H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin. Nomenclature H3K9me3 ...
which are known heterochromatic modifications. In Drosophila, Islands of retroelements are major components of the centromeres. In the yeast ''
Schizosaccharomyces pombe ''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measur ...
'' (and probably in other eukaryotes), the formation of centromeric heterochromatin is connected to
RNAi RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by ...
. 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,
neocentromere Neocentromeres are new centromeres that form at a place on the chromosome that is usually not centromeric. They typically arise due to disruption of the normal centromere. These neocentromeres should not be confused with “knobs”, which were al ...
s 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. The formation of a neocentromere must be coupled with the inactivation of the previous centromere, since chromosomes with two functional centromeres (
Dicentric chromosome 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 dicent ...
) 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.
Neocentromere Neocentromeres are new centromeres that form at a place on the chromosome that is usually not centromeric. They typically arise due to disruption of the normal centromere. These neocentromeres should not be confused with “knobs”, which were al ...
s lack the repetitive structure seen in normal centromeres which suggest that centromere formation is mainly controlled
epigenetically In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
. 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. Centromere repositioning and the formation of evolutionary new centromeres has been suggested to be a mechanism of speciation. Centromere proteins are also the autoantigenic target for some
anti-nuclear antibodies Antinuclear antibodies (ANAs, also known as antinuclear factor or ANF) are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human prote ...
, such as
anti-centromere antibodies Anti-centromere antibodies (ACAs; often styled solid, anticentromere) are autoantibodies specific to centromere and kinetochore function. They occur in some autoimmune diseases, frequently in limited systemic scleroderma (formerly called CREST sy ...
.


Dysfunction and disease

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. Instability of centromere repetitive DNA was recently shown in cancer and aging.


Repair of centromeric DNA

When DNA breaks occur at centromeres in the
G1 phase The G1 phase, gap 1 phase, or growth 1 phase, is the first of four phases of the cell cycle that takes place in eukaryotic cell division. In this part of interphase, the cell synthesizes mRNA and proteins in preparation for subsequent steps lead ...
of the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
, the cells are able to recruit the
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al repair machinery to the damaged site, even in the absence of a
sister chromatid A sister chromatid refers to the identical copies (chromatids) formed by the DNA replication of a chromosome, with both copies joined together by a common centromere. In other words, a sister chromatid may also be said to be 'one-half' of the dup ...
. 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.


Etymology and pronunciation

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


See also

*
Telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
* Chromatid * Diploid * Monopolin


References


Further reading

* * *


External links

* {{Autoantigens Chromosomes DNA replication