10.1: DNA structure

Nucleotides and basic DNA structure

The building blocks of DNA are nucleotides. The important components of the nucleotide are a nitrogenous (nitrogen-bearing) base, a five-carbon sugar (pentose), and a phosphate group. The nucleotide is named depending on the nitrogenous base. The nitrogenous base can be a purine, such as adenine (A) and guanine (G), or a pyrimidine, such as cytosine (C) and thymine (T). The purines have a double-ring structure with a six-membered ring fused to a five-membered ring. Pyrimidines are smaller in size; they have a single six-membered ring structure. The sugar is deoxyribose in DNA and ribose in RNA. The carbon atoms of the five-carbon sugar are numbered 1′, 2′, 3′, 4′, and 5′ (1′ is read as “one prime”). The phosphate, which makes DNA and RNA acidic, is connected to the 5′ carbon of the sugar by the formation of an ester linkage between phosphoric acid and the 5′-OH group (an ester is an acid + an alcohol). In DNA nucleotides, the 3′ carbon of the sugar deoxyribose is attached to a hydroxyl (OH) group (figures 10.1 and 10.2).

Figure 10.1: Basic structure of nucleotides including the sugar (ribose or deoxyribose), base (pyrimidine or purine), and phosphate groups.

Figure 10.2: Structure of pyrimidine and purine bases.

The nucleotides combine with each other to produce phosphodiester bonds. The phosphate residue attached to the 5′ carbon of the sugar of one nucleotide forms a second ester linkage with the hydroxyl group of the 3′ carbon of the sugar of the next nucleotide, thereby forming a 5′-3′ phosphodiester bond. In a polynucleotide, one end of the chain has a free 5′ phosphate, and the other end has a free 3′-OH. These are called the 5′ and 3′ ends of the chain.

Base-pairing takes place between a purine and pyrimidine on opposite strands, so that adenine and thymine are complementary base pairs, and cytosine and guanine are also complementary base pairs. The base pairs are stabilized by hydrogen bonds: adenine and thymine form two hydrogen bonds, and cytosine and guanine form three hydrogen bonds. The two strands are anti-parallel in nature; that is, the 3′ end of one strand faces the 5′ end of the other strand. The sugar and phosphate of the nucleotides form the backbone of the structure, whereas the nitrogenous bases are stacked inside, like the rungs of a ladder. The twisting of the two strands around each other results in the formation of uniformly spaced major and minor grooves.

DNA has a double helix structure and phosphodiester bonds; the dotted lines between thymine and adenine and guanine and cytosine represent hydrogen bonds. The major and minor grooves are binding sites for DNA-binding proteins during processes such as transcription (the copying of RNA from DNA) and replication (figure 10.3).

Figure 10.3: General structure and hydrogen bonding pattern of DNA.

DNA packaging and organization

Eukaryotic chromosomes consist of a linear DNA molecule complexed with protein (histones); this complex is called chromatin. Histones are evolutionarily conserved proteins that are rich in basic amino acids and form an octamer composed of two molecules of each of four different histones.

The DNA (remember, it is negatively charged because of the phosphate groups) is wrapped tightly around the histone core. This interaction is facilitated through electrostatic interactions. The negatively charged phosphate groups on the DNA backbone are attracted to a positively charged lysine on the exposed surface of histones. This nucleosome is linked to the next one with the help of a linker DNA. This is also known as the “beads on a string” structure. With the help of a fifth histone, a string of nucleosomes is further compacted into a 30 nm fiber, which is the diameter of the structure. Metaphase chromosomes are even further condensed by association with scaffolding proteins. At the metaphase stage, the chromosomes are at their most compact, approximately 700 nm in width (figure 10.4).

Figure 10.4: Organizational structure of DNA illustrating condensation and supercoiling into chromosomes.

In interphase, eukaryotic chromosomes have two distinct regions that can be distinguished by staining. The tightly packaged region is known as heterochromatin, and the less dense region is known as euchromatin.

Heterochromatin usually contains genes that are not expressed and is found in the regions of the centromere and telomeres.

The euchromatin usually contains genes that are transcribed, with DNA packaged around nucleosomes but not further compacted.

Histone tails can be modified through both methylation and acetylation, which will alter the histone:DNA interaction. Histone methylation can have variable impacts on a given gene locus leading to a change in transcription. Histone acetylation relaxes the interactions of histones and DNA by removing the positive charge on lysine residues allowing the DNA to be transcriptionally accessible (euchromatin). DNA methylation, specifically to CpG islands, globally represses transcription. These modifications on histones and DNA can result in epigenetic influences that have an impact on many biological processes.

Across the three billion base pair genome, genes are organized into clusters with only a fraction of the DNA coding for translated products. The remaining DNA was historically considered "junk," however, more recently there is a new appreciation for the roles of noncoding DNA regions. Only half of the genome is unique DNA sequence, and only 1.5 percent codes for mRNA (~20,000 protein-coding genes). The remaining sequence can be categorized as:

• Moderately repetitive: DNA containing ribosomal RNA (rRNA), tandem and nontandem repeats, and short and long interspersed nuclear elements (SINE and LINE).
• Transposable elements: These are movable elements, transposons or retrotransposons, that can result in disease-causing mutations if inserted into important genomic loci.
• Highly repetitive sequence: Satellites and mini satellites are regions of high sequence repetition (trinucleotide repeats) and are difficult to replicate. This can lead to expansions of these areas as well as mutations resulting in frame shifts or loss of translational starts.

References and resources

Text

Clark, M. A. Biology, 2nd ed. Houston, TX: OpenStax College, Rice University, 2018, Chapter 14: DNA Structure and Function.

Karp, G., and J. G. Patton. Cell and Molecular Biology: Concepts and Experiments, 7th ed. Hoboken, NJ: John Wiley, 2013, Chapter 10: The Nature of the Gene and the Genome, Chapter 12: The Cell Nucleus and the Control of Gene Expression, Chapter 13: DNA Replication.

Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 34, 38–40.

Nussbaum, R. L., R. R. McInnes, H. F. Willard, A. Hamosh, and M. W. Thompson. Thompson & Thompson Genetics  in Medicine, 8th ed. Philadelphia: Saunders/Elsevier, 2016, Chapter 2: The Introduction to the Human Genome.

Figures

Grey, Kindred, Figure 10.1 Basic structure of nucleosides including the sugar (ribose or deoxyribose), base (pyrimidine or purine) and phosphate groups. 2021. Chemical structure by Henry Jakubowski. https://archive.org/details/10.1_20210926. CC BY 4.0.

Grey, Kindred, Figure 10.2 Structure of pyrimidine and purine bases. 2021. Chemical structure by Henry Jakubowski. https://archive.org/details/10.2_20210926. CC BY 4.0.

Grey, Kindred, Figure 10.3 General structure and hydrogen bonding pattern of DNA. 2021. Chemical structure by Henry Jakubowski. https://archive.org/details/10.3_20210926. CC BY-SA 4.0. Added DNA double helix grooves by Biochemlife. CC BY-SA 4.0. From Wikimedia Commons.

Grey, Kindred, Figure 10.4 Organizational structure of DNA illustrating condensation and supercoiling into chromosomes. 2021. https://archive.org/details/10.4_20210926. CC BY-SA 4.0. Added DNA double helix grooves by Biochemlife. CC BY-SA 4.0. From Wikimedia Commons. And Figure 14.11. CC BY 4.0. From OpenStax.