Centromere

Centromere

Definition:

The centromere is a sequence of DNA that functions during cell division as an attachment point for proteins that link the chromosome to the mitotic spindle. This attachment is essential for the equal and orderly distribution of chromosome sets to daughter cells during mitosis and meiosis.

In simple words ‘Centromere’ is the region of the chromosome that is responsible for its segregation at mitosis and meiosis’

  • Centromere is also termed as primary constriction
  • The DNA in the centromere region of a chromosome is composed of tightly packed chromatin known as heterochromatin. Centromere region is rich in satellite DNA sequences.
  • Heterochromatin is very condensed and is therefore not transcribed. Due to its heterochromatin composition, the centromere region stains more darkly with dyes than the other regions of a chromosome
  • Chromosomes without a centromere cannot be drawn into the newly formed nuclei; these chromosomes are lost, often with catastrophic consequences to the cell.

Metaphase chromosome structure

  • Functional chromosomes contain centromeres, telomeres, and origins of replication. Telomeres are the stabilizing ends of a chromosome and origins of replication are sites where DNA synthesis begins.
  • Each metaphase chromosome consists of two sister chromatids, which are attached at the centromere. Each sister chromatid consists of a single molecule of DNA.
  • (At the time of mitosis, cells have already progressed through the S phase of the cell cycle and have replicated their DNA. Consequently, the chromosomes that become visible during metaphase are duplicated structures)

Each chromosome has two arms (Extending from either side of the centromere): p arm (shorter arm) and q arm (longer arm).

The number, sizes, and shapes of the metaphase chromosomes constitute the karyotype, which is distinctive for each species.  In most organisms, all cells have the same karyotype.

Figure 1: Structure of typical eukaryotic metaphase chromosome

Chromosome classification (Based on centromere position)

  • ‘Centro’ means center and ‘mere’ means part
  • But centromeres are not always located right at the center of a chromosome. They can have various positions along the chromosome.
  • For any particular chromosome, the position of the centromere is fixed.

On the basis of the location of the centromere, chromosomes are classified into four types:

1) Metacentric chromosome

Location of centromere: Centromere is approximately in the center of a chromosome (‘Meta’ means middle)

Example: In a normal human karyotype, five chromosomes are considered metacentric.

(Chromosomes 1, 3, 16, 19, and 20)

The centromere divides the chromosome into two arms. These are X-shaped chromosomes, with the centromere in the middle so that the two arms of the chromosomes are almost equal.

In some cases, a metacentric chromosome is formed by balanced translocation: the fusion of two acrocentric chromosomes to form one metacentric chromosome

2) Submetacentric chromosomes

Position of centromere: Centromere is closer to one end of the chromosome than the other

Example: Chromosome 5 (In humans)

Their shape is L shape. The length of p arm and q arm are unequal.

3) Acrocentric chromosome

Location of centromere: Centromere is very near to one end of the chromosome.

(‘Acro’ means top or extremity)

Example: The human genome includes six acrocentric chromosomes (Chromosome 13, 14, 15, 21, 22 and Y chromosome)

The p arm is too short and hard to observe. But still it is present.

4) Telocentric chromosome

Location of centromere: Centromere is located at the terminal end of the chromosome.

(‘Telo’ means last or end)

Example: All house mouse chromosomes are telocentric

(Humans do not possess telocentric chromosomes)

Their shape is similar to letter “i” during anaphase.

5) Holocentric chromosome

  • 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.
  • The well-known example is the nematode Caenorhabditis elegans.
Figure 2: Types of chromosome based on position of centromere (The shape of the chromosome during anaphase is determined by the position of the centromere during metaphase)

Chromosome classification (Based on number of centromere)

According to the number of the centromere the eukaryotic chromosomes may be:

1)  Acentric chromosome: Without any centromere

2) Monocentric chromosome: with one centromere

3) Dicentric chromosome: with two centromeres

4) Polycentric chromosome: with more than two centromeres

Structure of centromere

  • Centromeres are easily seen in the light microscope following chromosome condensation. They appear as a constricted region where the daughter chromosomes remain attached to each other.
  • In non-dividing cells the centromere region is heterochromatic, which means that it remains relatively condensed compared to the rest of the chromatin that contains active genes (euchromatin).
  • Yeast centromeres are very simple but mammalian centromere DNA has not been extensively characterized because it consists largely of multiple repeats of simple sequence DNA. Because of the repetitive nature of centromeric DNA these region are difficult to clone. They are missing from the human genome database.
  • The centromeres of Saccharomyces cerevisiae have been isolated and studied. It generally contains simple-sequence 0f DNA. The sequences essential to centromere function are about 130 bp long and are very rich in AUT pairs.
  • The centromeric sequences of higher eukaryotes are much longer and consist of thousands of tandem copies of one or a few short sequences of 5 to 10 bp, in the same orientation.
  • In humans the dominant repeat is α satellite DNA, a 171 bp sequence that is repeated about 18,000 times at an average centromere.
Figure 3: Structure of Human centromere region

Functions of centromere

Centromeres are responsible for two major functions.

1) The centromere is the specialized DNA sequence of a chromosome that links a pair of sister chromatids (a dyad)

  • One major function of a centromere is joining the sister chromatids. The two copies of a replicated chromosome are called sister chromatids. The centromere helps to hold the duplicated chromosomes together until they are ready to be moved apart.
  • Cohesins are proteins that keep the chromatids stuck together. At the beginning of mitosis, the cohesins are distributed evenly along the chromatids, so they are stuck together along their whole lengths.
  • By metaphase, when all the chromosomes are lined up at the middle of the cell just before they separate, the cohesins are only located at the centromere regions, so the sister chromatids are only connected there.

2) The centromere is the attachment point for spindle microtubules, which are the filaments responsible for moving chromosomes during cell division.

  • In M phase, the centromere attaches the duplicated chromosomes to the mitotic spindle so that one copy is distributed to each daughter cell during mitosis.
  • Before cell division, a disc shaped protein complex called the kinetochore assembles on the surface of the centromere to which microtubules of the spindle later attach (Spindle fibers attach to the centromere via the kinetochore)
  • On each chromatid, the kinetochore forms at the centromere region of the DNA. Once all of the chromatids are attached to the mitotic spindle, the microtubules pull the sister chromatids apart into the two future daughter cells.

(If a chromosome had two centromeres, it could be broken apart by being pulled in two different directions during mitosis. If it had no centromeres, it would assort randomly into the daughter cells and would eventually be lost)

Kinetochore structure

  • The actual location on the centromere where the spindle fiber attachment occurs is called the kinetochore and is composed of both DNA and protein.
  • The DNA sequence within these regions is called CEN DNA.
  • Typically CEN DNA is about 220 base pairs long and consists of several sub-domains, CDEI, CDE-II and CDE-III.
  • Mutations in the first two sub-domains have no effect upon segregation, but a point mutation in the CDE-III sub-domain completely eliminates the ability of the centromere to function during chromosome segregation.
  • Therefore CDE-III must be actively involved in the binding of the spindle fibers to the centromere.
Figure 4: Structure of kinetochore

How centromere behaves during mitosis and meiosis?

  • During mitosis, the centromere that is shared by the sister chromatids must divide so that the chromatids can migrate to opposite poles of the cell. On the other hand, during the first meiotic division the centromere of sister chromatids must remain intact whereas during meiosis II they must act as they do during mitosis. Therefore the centromere is an important component of chromosome structure and segregation.
  • Centromeres are the first parts of chromosomes to be seen moving towards the opposite poles during anaphase. The remaining regions of chromosomes lag behind and appear as if they were being pulled by the centromere.

Disfunctioning of centromere

  • When centromeres do not function properly, cells cannot successfully divide. Any attempt to do so results in daughter cells which do not have the genetic instructions they need to survive.
  • Centromere dysfunction leading to problems with chromosome sorting is believed to play a role in many instances of miscarriage, in which inherited centromere disorders may result in early embryonic death.
  • Centromere dysfunction is also suspected to play a role in cancer cells, which display massive chromosome imbalance of the type that would be expected if the sorting of chromosomes during cell division failed.

 

 

 

 

 

 

 

 

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