Genetics, DNA Packaging

Excerpt

Although the DNA helical diameter is only 2 nm, the entire DNA strand in a single cell will stretch roughly 2 meters when completely unwound. The entire DNA strand must fit within the nucleus of a cell, so it must be very tightly packaged to fit. This is accomplished by wrapping the DNA around structural histone proteins, which act as scaffolding for the DNA to be coiled around. The entire structure is called a nucleosome, each of which includes an octamer of histone proteins and 146 to 147 base pairs of DNA. The millions of nucleosomes tightly coil the continuous DNA strand into chromatin which is further condensed into the chromosome classically visualized during cell division.

The nucleosome structure was first described in 1974 by Roger Kornberg who, with evidence from biochemical experiments, X-ray diffraction studies, and electron microscopy images, proposed the nucleosome was comprised of repeating units of eight histone proteins and about 200 DNA base pairs. In the same year, Markus Noll gave a visually interpretable result to understand how DNA wraps around the nucleosomes. The results of his experiments showed that DNA wrapped was cleaved when exposed to DNAse I, which suggested that the enzyme must have had access to the DNA. The results of this experiment favored the theory that DNA was wound on the outside of the nucleosome unit and supported the nucleosome structure proposed by Kornberg, with each nucleosome consisting of approximately 200 DNA base pairs.

The tight structure of chromatin brings about the problem of accessibility to the DNA by enzymes involved in DNA replication and transcription. Chromatin exists in one of two states: heterochromatin, which is condensed and allows little access by transcription enzymes, and euchromatin, which is loose to allow for interaction with transcription enzymes. The transition between these two states is determined by interactions between the DNA and histone proteins via post-translational modifications to the histone proteins like methylation and acetylation. Methylation generally increases interactions between the DNA and histone, thus suppressing gene expression, whereas acetylation will loosen interactions resulting in greater access by transcription enzymes resulting in increased gene expression. The post-translational modifications to histone proteins underlie the mechanisms of epigenetics, which are defined as alterations to gene expression without changes to the DNA sequence.

The ability for DNA packaging to be modified at various stages of the cell cycle is important in both DNA replication and cell division as well as transcription. Replication occurs at many origins of replication throughout the DNA strand to accelerate the replication of the entire genome, with each origin separated by approximately 100,000 base pairs. The DNA does not interact with histones during this process to allow for the propagation of the polymerase enzymes. However, when the process is complete, the DNA must reintegrate with the histones to reform nucleosomes and eventually the supercoiled chromosome structure during mitosis. Following cell division, the DNA must again separate from the histone proteins to undergo transcription. This capability for the DNA-histone interactions to be modulated is crucial for the proper growth and function of a cell with malfunctions contributing to disease like hypermethylation in cancer.