Structure of Chromosome at Molecular Level (Nucleosome structure)

Molecular Structure of Chromosome

Molecular Structure of Chromosome 

In the past, study of chromosome ultrastructure was an important area, where electron microscope had failed to give us a clear picture of organization of DNA. For the study of chromosomes with the help of electron microscope, whole chromosome mounts as well as sections of chromosomes were studied. Such studies had demonstrated that chromosomes have very fine fibrils of 2 nm- 4 nm thickness. Since DNA is 2 nm wide, there is possibility that a single fibril corresponds to a single DNA molecule. Further, if a single chromatid has a single long DNA molecule, as has been proved, we have no choice but to believe that DNA should be present in a coiled or folded manner. This can also be inferred from the fact that the thickness of a chromosome is usually hundred times that of DNA and the length of DNA found in a chromosome is several thousand times the length of the chromosomes. The manner of coiling and folding of DNA was a matter of debate and dozens of important models for this purpose were available. A popular model was the folded fiber model given by E.J. Du Praw in 1965. However, the most important and universally accepted model is nucleosome model proposed in 1974.

Molecular Structure of Chromosome

  1. Nucleosome (subunit of chromatin)-

    In 1974, R.D. Kornberg and J.O. Thomas proposed an attractive model for basic chromatin structure involving DNA and histones. They suggested that DNA interacts with a tetramer (H3, H4,) and two molecules of an oligomer (H2A-H2B), so that a tetramer involving two molecules each of the histones H3 and H4, is associated with two molecules each of the histones H2A and H2B and with 200 base pairs of DNA. This makes a repeating unit. One olecule of H1 is also associated with each repeating unit. They also proposed that the tetramer makes the core of the unit and oligomers determine the spacing thus giving a flexible structure. This model is supported from biochemical and electron microscopy results. P. Oudet et al. (1975) proposed the term nucleosome for repeating units which were observed as beads on strings (or string on beads) under electron microscope.

Nucleosome (12.5 nm in diameter) = 200 base pairs + 2 molecules each of H2A, H2B, H3, H4.

Nucleosome has a core, which consists of a chain of DNA, 140 base pairs (rather than 200 base pairs) making 14 turns and coiled around an octamer consisting of two molecules each of H2A, H2B, H3 and H4. Thus it makes a string (DNA chain) on beads rather than beads on string. One molecule of H1 holds the two ends of DNA in a nucleosome and is thus not an integral part of a nucleosome. The nucleosome core having 140

base pairs (instead of 200) is an enzymatically reduced form of the nucleosome. The nucleosomes are once again coiled into what is called a solenoid, so that a solenoid model is proposed.

  1. Telomere-

    The structure of telomeres in a wide variety of organisms has been studied to demonstrate that telomeres are highly conserved elements throughout the eukaryotes, both in structure and function. Telomeric DNA has been shown to consist of simple randomly repeated sequences, characterized by clusters of G residues in one strand and C residues in the other. Another feature is a 3 overhang (12-16 nucleotides in length) of the G-rich strand. Some of the telomeric DNA sequences found in eukaryotes are given in Table.

The same repeated sequence is found at the ends of all chromosomes in a species and the same telomere sequence may occur in widely divergent species, such as humans, some acellualr slime molds (trypanosomes) and fungi like neurospora. At every telomere, as much as 10 kilobases of this repeat sequence may occur. The telomeric DNA is also complexed with non-histone proteins, the complex structure being associated with nuclear lamina, as shown in Oxytricha, a ciliated protozoan. The telomeric DNA is synthesized under the influence of telomerase, an enzyme which has been shown to be a ribonucleoprotein, whose RNA component works as a template for synthesis of telomeric DNA repeats and protein component has reverse transcriptase (RT) activity.

Table: Repeated telomeric DNA sequences in some organisms.

Telomeric DNA repeat Organisms
AGGTT Homo sapiens, Physarum, Neurospora, Tryponosoma
GGGGTT Tetrahymena, Glaucoma
GGG(G/T)TT Paramecium
GGGGTTTT Oxytricha, Stylomychia, Euplotes
AGGG(T/C)TT Plasmodium
AGGGTTT Arabidopsis (a higher plant)
AGGGTTTT Chlamydomonas

(A)G(2-5)TTAC

Schizosaccharomyces pombe (fission yeast)

G(1-3)T

Saccharomyces cerevisiae (budding yeast)
G(1-8)A Dictyostelium (a mold)

Recently (in 1997), proteins have been isolated from telomerase in yeast and a ciliated protozoan (Euplotes) which could be the RT component of telomerase. These were p123 in Euplotes and Est2 in yeast. Efforts have also been made to understand, how the telomere length is monitored in chromosomes, because uncontrolled activity of telomerase will lead to indefinite elongation of telomeres, Proteins binding to telomere repeats have been identified, which block the elongation of telomeres. These include Raplp in budding yeast, Tazlp in fission yeast and TRF in humans. In the year 1998, two additional groups of proteins, namely Ku and Sir proteins were shown to be associated with telomeres. Although these were earlier shown to be involved in DNA repair, during 1998, these were shown to be involved in telomere replication and telomere silencing (genes adjacent to telomere are subject to silencing). These Ku and Sir proteins may also play some role in regulating the length of the telomere. However, we still do not know, how the cell measures the telomere length, and how is this information used to regulate the length of telomeres.

  1. Kinetochore and Centromeric DNA sequences-

    Centromere is a unique region of a chromosome characterized by a constriction, where the two chromatids remain joined together after chromosomes replication. On each of these centromeres, specialized protein complexes known as kinetochores assemble. Each chromosome has two kinetochores, one on each sister chromatid, facing in opposite directions. These kinetochores are the sites for binding of kinetochore microtubules, which take part in spindle assembly and assist in the movement of chromosomes during anaphase.

The DNA sequences representing the centromere contain the information specifying the assembly of kinetochore. These centromeric DNA sequences have been isolated and characterized in a number of organisms but, unlike the telomeric sequences, these sequences have not been found to be conserved. However, they include both unique and repetitive DNA sequences, several kilobase or megabase in length. For instance, in mammals centromeres consist of many different and much longer DNA sequences, that are both unique and repetitive in nature. It is believed that much of the repetitive DNA sequence (called satellite DNA) in mammalian centromeres is required for the special chromatin organization at the centromere. However, it is shown that the tandemly repeated DNA families are poorly conserved between species. However, a 17bp long sequence called CENP-B box, (meant for the binding of a protein, CENP-B) seems to be conserved over diverse animal systems. The centromere protein B (CENP-B), is found associated with most human and mouse centromeres and its amino acid sequence is highly conserved among mammals. However, the binding of CENP-B protein is neither necessary nor sufficient for centromere function.

The best studied satellite sequence is alpha-satellite, which is found in all human and primate centromeres. The basic units of alpha-satellite are diverged, and consist of 171 bp long monomers (arranged in a tandem manner) that are organized into higher order repeat units. CENP-B box is found only in a subset of these monomers. Alpha-satellite DNA is also believed to play an important role in centromere function. Similarly, minor satellite (monomer sequence of 300bp) in mouse also represents repetitive DNA elements related to centromeric function.

Centromeric sequences have also been isolated in a number of cereals and other members of grass family but none of them could be shown to perform centromere function. These include

  • CCS1 from Triticeae (CCS-Cereal centromere sequence);
  • BCS1 and BCS2 from barley (BCS-barley centromeric sequence);
  • RCS1 from rice (RCS=rice centromeric sequence);
  • MCS1 from maize (MCS-maize centromeric sequence);
  • pSau3A9 (745bp) isolatea from sorghum has also been shown to be conserved in distantly related monocot plant species but not in dicotyledons.

The isolation and cloning of functional centromeric DNA sequences as above, is a pre-requisite for construction of artificial chromosomes. The two other sequences; necessary for this purpose are telomeres and replication origins. Such artificial chromosomes have already been constructed in yeast and are called yeast artificial chromosomes or YACs. Mammalian (or human) artificial chromosomes (MACs or HACs) have also been reported in 1997. In future, construction of plant artificial chromosomes (PACS) may also become possible.

Function of chromosomes

The function of chromosomes is to carry the genetic information from one cell generation to another. The DNA, which is the only permanent component of chromosome structure, is the sole genetic material (consult Chapter 19 of Genetics). The manner in which DNA stores the genetic information will be dealt elsewhere. The replication of chromosome depends on a very precise replication of DNA.

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