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 attach to the centromere via the kinetochore.
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 signaling 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 characterized 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.
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. |
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]
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 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 means that the centromere is positioned below the middle, with one chromosome arm shorter than the other, often resulting in an L shape.
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 has six acrocentric chromosomes, including five autosomal chromosomes (13, 14, 15, 21, 22) and the Y chromosome.
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 regions (NORs), from which ribosomal RNA is transcribed. However, a proportion of acrocentric p-arms in cell lines and tissues from normal human donors do not contain detectable NORs. [4] 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).
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. 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 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 humans 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 chromosomes' centromeres are located between the middle and the end of the chromosomes, but reside closer to the end of the chromosomes.
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.
A dicentric chromosome 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. [5] The formation of dicentric chromosomes has been attributed to genetic processes, such as Robertsonian translocation [6] and paracentric inversion. [7] Dicentric chromosomes can have a variety of fates, including mitotic stability. [8] 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 division. [9]
For example, human chromosome 2, which is believed to be the result of a Robertsonian translocation at some point in the evolution between the great apes and Homo, has a second, vestigial, centromere near the middle of its long arm. [10]
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. [11]
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. [12] The nematode, Caenorhabditis elegans, is a well-known example of an organism with holocentric chromosomes, [13] 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. [14] 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. [15] 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. [16] 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. [17]
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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 | — |
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: [18]
Group | Chromosomes | Features |
---|---|---|
Group A | Chromosome 1-3 | Large, metacentric and submetacentric |
Group B | Chromosome 4-5 | Large, submetacentric |
Group C | Chromosome 6-12, X | Medium-sized, submetacentric |
Group D | Chromosome 13-15 | Medium-sized, acrocentric, with satellite |
Group E | Chromosome 16-18 | Small, metacentric and submetacentric |
Group F | Chromosome 19-20 | Very small, metacentric |
Group G | Chromosome 21-22, Y | Very small, acrocentric, with satellite |
There are two types of centromeres. [19] 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. [20] Centromere satellites are hypothesized to evolve by a process called layered expansion. They evolve rapidly between species, and analyses in wild mice show that satellite copy number and heterogeneity relates to population origins and subspecies. [21] Additionally, satellite sequences may be affected by inbreeding. [21]
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. [20]
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. [22] 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. [23] 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.
On the other hand, thanks to comparisons of the centromeres in the X chromosomes, epigenetic and structural variations have been seen in these regions. In addition, a recent assembly of the human genome has detected a possible mechanism of how pericentromeric and centromeric structures evolve, through a layered expansion model for αSat sequences. This model proposes that different αSat sequence repeats emerge periodically and expand within an active vector, displacing old sequences, and becoming the site of kinetochore assembly. The αSat can originate from the same, or from different vectors. As this process is repeated over time, the layers that flank the active centromere shrink and deteriorate. This process raises questions about the relationship between this dynamic evolutionary process and the position of the centromere. [24]
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. [25] 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 [26] which are known heterochromatic modifications. In Drosophila, Islands of retroelements are major components of the centromeres. [27]
In the yeast Schizosaccharomyces pombe (and probably in other eukaryotes), the formation of centromeric heterochromatin is connected to RNAi. [28] 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. [29] [30] 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. [31] [32] 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. [31] Centromere repositioning and the formation of evolutionary new centromeres has been suggested to be a mechanism of speciation. [33]
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. [34] Instability of centromere repetitive DNA was recently shown in cancer and aging. [35]
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. [36] 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. [36]
The word centromere ( /ˈsɛntrəˌmɪər/ [37] [38] ) uses combining forms of centro- and -mere , yielding "central part", describing the centromere's location at the center of the chromosome.
The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.
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 links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932.
Robertsonian translocation (ROB) is a chromosomal abnormality where the entire long arms of two different chromosomes become fused to each other. It is the most common form of chromosomal translocation in humans, affecting 1 out of every 1,000 babies born. It does not usually cause medical problems, though some people may produce gametes with an incorrect number of chromosomes, resulting in a risk of miscarriage. In rare cases this translocation results in Down syndrome and Patau syndrome. Robertsonian translocations result in a reduction in the number of chromosomes. A Robertsonian evolutionary fusion, which may have occurred in the common ancestor of humans and other great apes, is the reason humans have 46 chromosomes while all other primates have 48. Detailed DNA studies of chimpanzee, orangutan, gorilla and bonobo apes has determined that where human chromosome 2 is present in our DNA in all four great apes this is split into two separate chromosomes typically numbered 2a and 2b. Similarly, the fact that horses have 64 chromosomes and donkeys 62, and that they can still have common, albeit usually infertile, offspring, may be due to a Robertsonian evolutionary fusion at some point in the descent of today's donkeys from their common ancestor.
An isochromosome is an unbalanced structural abnormality in which the arms of the chromosome are mirror images of each other. The chromosome consists of two copies of either the long (q) arm or the short (p) arm because isochromosome formation is equivalent to a simultaneous duplication and deletion of genetic material. Consequently, there is partial trisomy of the genes present in the isochromosome and partial monosomy of the genes in the lost arm.
A micronucleus is a small nucleus that forms whenever a chromosome or a fragment of a chromosome is not incorporated into one of the daughter nuclei during cell division. It usually is a sign of genotoxic events and chromosomal instability. Micronuclei are commonly seen in cancerous cells and may indicate genomic damage events that can increase the risk of developmental or degenerative diseases.
An acentric fragment is a segment of a chromosome that lacks a centromere.
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 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. Their existence has been linked to certain natural phenomena such as irradiation and have been documented to underlie certain clinical syndromes, notably Kabuki syndrome. The formation of dicentric chromosomes and their implications on centromere function are studied in certain clinical cytogenetics laboratories.
Aurora kinase B is a protein that functions in the attachment of the mitotic spindle to the centromere and in cytokinesis.
Centromere protein B also known as major centromere autoantigen B is an autoantigen protein of the cell nucleus. In humans, centromere protein B is encoded by the CENPB gene.
Centromere protein A, also known as CENPA, is a protein which in humans is encoded by the CENPA gene. CENPA is a histone H3 variant which is the critical factor determining the kinetochore position(s) on each chromosome in most eukaryotes including humans.
Centromere-associated protein E is a protein that in humans is encoded by the CENPE gene.
Centromere protein C 1 is a protein that in humans is encoded by the CENPC1 gene.
Centromere protein H is a protein that in humans is encoded by the CENPH gene. It is involved in the assembly of kinetochore proteins, mitotic progression and chromosome segregation.
Centromere protein I is a protein that in humans is encoded by the CENPI gene.
Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them. The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy leading to aneuploidy. In other words, the daughter cells do not have the same number of chromosomes as the cell they originated from. Chromosomal instability is the most common form of genetic instability and cause of aneuploidy.
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 also described as “neocentromeres” in maize in the 1950s. Unlike most normal centromeres, neocentromeres do not contain satellite sequences that are highly repetitive but instead consist of unique sequences. Despite this, most neocentromeres are still able to carry out the functions of normal centromeres in regulating chromosome segregation and inheritance. This raises many questions on what is necessary versus what is sufficient for constituting a centromere.
Robin Campbell Allshire is Professor of Chromosome Biology at University of Edinburgh and a Wellcome Trust Principal Research Fellow. His research group at the Wellcome Trust Centre for Cell Biology focuses on the epigenetic mechanisms governing the assembly of specialised domains of chromatin and their transmission through cell division.
Kaustuv Sanyal is an Indian molecular biologist, mycologist and a professor at the Molecular Biology and Genetics Unit of the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR). He is known for his molecular and genetic studies of pathogenic yeasts such as Candida and Cryptococcus). An alumnus of Bidhan Chandra Krishi Viswavidyalaya and Madurai Kamaraj University from where he earned a BSc in agriculture and MSc in biotechnology respectively, Sanyal did his doctoral studies at Bose Institute to secure a PhD in Yeast genetics. He moved to the University of California, Santa Barbara, USA to work in the laboratory of John Carbon on the discovery of centromeres in Candida albicans. He joined JNCASR in 2005. He is a member of the Faculty of 1000 in the disciplines of Microbial Evolution and Genomics and has delivered invited speeches which include the Gordon Research Conference, EMBO conferences on comparative genomics and kinetochores. The Department of Biotechnology of the Government of India awarded him the National Bioscience Award for Career Development, one of the highest Indian science awards, for his contributions to biosciences, in 2012. He has also been awarded with the prestigious Tata Innovation Fellowship in 2017. The National Academy of Sciences, India elected him as a fellow in 2014. He is also an elected fellow of Indian Academy of Sciences (2017), and the Indian National Science Academy (2018). In 2019, he has been elected to Fellowship in the American Academy of Microbiology (AAM), the honorific leadership group within the American Society for Microbiology.
Holocentric chromosomes are chromosomes that possess multiple kinetochores along their length rather than the single centromere typical of other chromosomes. They were first described in cytogenetic experiments in 1935. Since this first observation, the term holocentric chromosome has referred to chromosomes that: i) lack the primary constriction corresponding to the centromere observed in monocentric chromosomes; and ii) possess multiple kinetochores dispersed along the entire chromosomal axis, such that microtubules bind to the chromosome along its entire length and move broadside to the pole from the metaphase plate. Holocentric chromosomes are also termed holokinetic, because, during cell division, the sister chromatids move apart in parallel and do not form the classical V-shaped figures typical of monocentric chromosomes.
The monocentric chromosome is a chromosome that has only one centromere in a chromosome and forms a narrow constriction.
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