The centromere is the part of a chromosome that links sister chromatids. During mitosis,
spindle fibers attach to the centromere via the kinetochore. Centromeres were first defined
as genetic loci that direct the behavior of chromosomes. Their physical role is to act
as the site of assembly of the kinetochore - a highly complex multiprotein structure
that is responsible for the actual events of chromosome segregation - e.g. 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.
There are broadly speaking two types of centromeres. "Point centromeres" bind to specific proteins
that recognise 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 where two identical sister chromatids are
most closely in contact. When cells enter mitosis, the sister chromatids are linked
all 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, the last place where
they are linked with one another is in the chromatin in and around the centromere.
Positions Each chromosome has two arms, labeled p and
q. The p arm is named for "petit" meaning 'small'; the q arm is named q simply because
it follows p in the alphabet. They can be connected in either metacentric, submetacentric,
acrocentric or telocentric manner. 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, two chromosomes are considered
metacentric: chromosomes 1 and 3. In some cases, a metacentric chromosome is formed
by balanced translocation: the fusion of two acrocentric chromosomes to form one metacentric
chromosome. Submetacentric
If arms' lengths are unequal, the chromosome is said to be submetacentric.
Acrocentric If the p arm is so short that it is hard to
observe, but still present, then the chromosome is acrocentric. The human genome includes
six acrocentric chromosomes: 13, 14, 15, 21, 22, and Y.
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; in this case, because more species are extant, it is apparent
that the evolutionary sequence is a reduction of two acrocentric chromosomes in the great
apes to one metacentric chromosome in humans. Telocentric
A telocentric chromosome's centromere is located at the terminal end of the chromosome. Telomeres
may extend from both ends of the chromosome. 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.
Holocentric With holocentric chromosomes, the entire length
of the chromosome acts as the centromere. 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. Human Chromosomes
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 where the sequence
within individual repeat elements is similar but not identical. In humans, the primary
centromeric repeat unit is called α-satellite, although a number of other sequence types
are found in this region. 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 and contains two highly conserved DNA sequences that serve as binding sites for
essential kinetochore proteins. 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.
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 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 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 which are known heterochromatic modifications.
In the yeast Schizosaccharomyces pombe, the formation of centromeric heterochromatin is
connected to RNAi. 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. The formation of a neocentromere must be coupled
with the inactivation of the previous centromere, since chromosomes with two functional centromeres
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. See also
Cell biology Chromatid
Diploid Genetics
Monopolin References
Further reading Mehta, G. D.; Agarwal, M.; Ghosh, S. K.. "Centromere
Identity: a challenge to be faced". Mol. Genet. Genomics 284: 75–94. doi:10.1007/s00438-010-0553-4.
PMID 20585957. Lodish, Harvey; Berk, Arnold; Kaiser, Chris
A.; Krieger, Monty; Scott, Matthew P.; Bretscher, Anthony; Ploegh, Hiddle; Matsudaira, Paul.
Molecular Cell Biology. New York: W.H. Freeman. ISBN 978-0-7167-7601-7.
Nagaki, Kiyotaka; Cheng, Zhukuan; Ouyang, Shu; Talbert, Paul B; Kim, Mary; Jones, Kristine
M; Henikoff, Steven; Buell, C Robin; Jiang, Jiming. "Sequencing of a rice centromere uncovers
active genes". Nature Genetics 36: 138–45. doi:10.1038/ng1289. PMID 14716315. Lay summary
– Science Daily.