Packaging Of Dna Molecules Into Chromosomes

Eukaryotic Chromosomes and Chromatin Structure

A human cell contains 46 chromosomes (23 pairs), each of which is a single DNA molecule bundled up with various proteins. On average, each human chromosome contains about 1.3 x 108 base pairs (bp) of DNA. If the DNA in a human chromosome were stretched as

1400 nm

DNA has to be highly compacted in order to

1400 nm

DNA has to be highly compacted in order to nucleosomes ("beads on a string")

Figure 4.5. How DNA is packaged into chromosomes.

nucleosomes ("beads on a string")

Figure 4.5. How DNA is packaged into chromosomes.

far as it would go without breaking it would be about 5 cm long, so the 46 chromosomes in all represent about 2 m of DNA. The nucleus in which this DNA must be contained has a diameter of only about 10^.m, so large amounts of DNA must be packaged into a small space. This represents a formidable problem that is dealt with by binding the DNA to proteins to form chromatin. As shown in Figure 4.5, the DNA double helix is packaged at both small and larger scales. In the first stage, shown on the right of the figure, the DNA double helix with a diameter of 2 nm is bound to proteins known as histones. Histones are positively charged because they contain high amounts of the amino acids arginine and lysine (page 185) and bind tightly to the negatively charged phosphates on DNA. A 146 bp length of DNA is wound around a protein complex composed of two molecules each of four different histones—H2A, H2B, H3, and H4—to form a nucleosome. Because each nucleosome is separated from its neighbor by about 50 bp of linker DNA, this unfolded chromatin state looks like beads on a string when viewed in an electron microscope. Nucleosomes undergo further packaging. A fifth type of histone, H1, binds to the linker DNA and pulls the nucleosomes together helping to further coil the DNA into chromatin fibers 30 nm in diameter, which are referred to as 30-nm solenoids. The fibers then form loops with the help of a class of proteins known as nonhistones, and this further condenses the DNA (panels on left-hand side of Fig. 4.5) into a higher order set of coils in a process called supercoiling.

In a normal interphase cell about 10% of the chromatin is highly compacted and visible under the light microscope (page 57). This form of chromatin is called heterochromatin and is the portion of the genome where no RNA synthesis is occurring. The remaining interphase chromatin is less compacted and is known as euchromatin.

Chromatin is in its most compacted form when the cell is preparing for mitosis, as shown at the top left of Figure 4.5. The chromatin folds and condenses further to form the 1400-nm-wide chromosomes we see under the light microscope. Because the cell is to divide, the DNA has been replicated, so that each chromosome is now formed by two chromatids, each one a DNA double helix. This means the progeny cell, produced by division of the progenitor cell, will receive a full set of 46 chromosomes. Figure 4.6 is a photograph of human chromosomes as they appear at cell division.

Prokaryotic Chromosomes

The chromosome of the bacterium E. coli is a single circular DNA molecule of about 4.5 x 106 base pairs. It has a circumference of 1 mm, yet must fit into the 1-^.m cell, so like eukaryotic chromosomes it is coiled, supercoiled, and packaged with basic proteins that are similar to eukaryotic histones. However, an ordered nucleosome structure similar to the "beads on a string" seen in eukaryotic cells is not observed in prokaryotes. Prokaryotes do not have nuclear envelopes so the condensed chromosome together with its associated proteins lies free in the cytoplasm, forming a mass that is called the nucleoid to emphasize its functional equivalence to the eukaryotic nucleus.

Plasmids

Plasmids are small circular minichromosomes found in bacteria and some eukaryotes. They are several thousand base pairs long and are probably tightly coiled and supercoiled inside the cell. Plasmids often code for proteins that confer resistance to a particular antibiotic. In Chapter 7 we describe how plasmids are used by scientists and genetic engineers to artificially introduce foreign DNA molecules into bacterial cells.

Viruses (page 11) rely on the host cell to make more virus. Once viruses have entered cells, the cells' machinery is used to copy the viral genome. Depending on the virus type, the genome may be single- or double-stranded DNA, or even RNA. A viral genome is packaged within a protective protein coat. Viruses that infect bacteria are called bacteriophages. One of these, called lambda, has a fixed-size DNA molecule of 4.5 x 104 base pairs. In contrast, the bacteriophage M13 can change its chromosome size, its protein coat expanding in parallel to accommodate the chromosome. This makes M13 useful in genetic engineering (Chapter 7).

IN DEPTH 4.2 DNA—A Gordian Knot_

At the start of his career Alexander the Great was shown the Gordian Knot, a tangled ball of knotted rope, and told that whoever untied the knot would conquer Asia. Alexander cut through the knot with his sword. A similar problem occurs in the nucleus, where the 46 chromosomes form 2 m of tangled, knotted DNA. How does the DNA ever untangle at mitosis? The cell adopts Alexander's solution—it cuts the rope. At any place where the DNA helix is under strain, for instance, where two chromosomes press against each other, an enzyme called topoisomerase II cuts one chromosome double helix so that the other can pass through the gap. Then, surpassing Alexander, the enzyme rejoins the cut ends. Topoisomerases are active all the time in the nucleus, relieving any strain that develops in the tangled mass of DNA.

Viruses

chromosome under tension

■^•topoisomerase II moves to the region of most strain topoisomerase II

topoisomerase II

1st chromosome is bound to the enzyme topoisomerase II

2nd chromosome is bound to the enzyme topoisomerase II

1st chromosome is bound to the enzyme topoisomerase II

2nd chromosome is bound to the enzyme topoisomerase II

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