All cells within a complex multicellular organism such as a human being contain DNA. All the DNA together make up that organisms genome. There are many different types of cells within a complex organism. What, then makes a cardiomyocyte different than a hepatocyte? The answer lies within how each cell controls its genome. DNA consists of genes, which are short sequences of nucleic acids that code for particular molecular structures or protein that carries out a specialized function. Each cell can control its unique set of genes. Some are expressed, and others are repressed. This dictates cellular morphology and function. That is how a myocyte differs from a hepatocyte. Its not the DNA itself. All cells contain the same DNA. Rather, it’s how each cell is individualized, and controls how it uses the set of DNA. This expression and repression is highly regulated by cues both within and extrinsic to the cell. This article will serve to cover the first part of what DNA actually is and how it codes for specific polypeptides that carry out downstream functions. This is the central dogma of life.
Nucleic acids are what transfers genetic material as well as participate in cell signaling and other metabolic processes. Often considered the building blocks of cells. There are two main categories of nucleic acids; Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Both DNA and RNA are polymers of nucleotides. Both RNA and DNA structures are similar in that they consist of a sugar (either Ribose, or deoxyribose) with a nitrogen containing base (either a pyrimidine or purine) bonded to a phosphate group, except that DNA does not have a hydroxide group at Carbon-2, where as RNA does.
Nitrogenous bases are categorized as either a pyrimidine or a purine. A pyrimidine is a heterocyclic aromatic ring structure, whereas a purine is a two ringed heterocyclic aromatic ring. The pyrimidines are Uracil, which only exists in RNA, thymine, which only exists in DNA, and cytosine which coexists. The purines are adenine and guanine, which coexist in both DNA and RNA. Base-pairing is what creates the characteristic double-helix feature of DNA, and the single-stranded RNA structure. Each base-pair consists of one pyrimidine and one purine which are called base complements. In DNA, thymine always binds adenine (T-A), and guanine always binds to cytosine (G-C) through double or triple hydrogen bonds.
DNA being a double helix is proven to be advantageous in multiple ways; the nitrogenous base which contains the nucleic information is locked within the complex, facing each other in the centre of the molecule, as opposed to in RNA, where the nucleic acid base is exposed to the cellular environment which provides more opportunity for it to be mutated. DNA is more chemically stable than RNA and less susceptible to degradation. Having two complementary strands allows for greater proof-reading mechanisms. Thymine is much more stable than uracil (RNA). Due to deamination cytosine is often changed to uracil, which in DNA is quickly corrected because uracil is not supposed to be there. In RNA, it’s impossible for the cell to know if it’s truly supposed to be there or not.
DNA replication is the biological process of producing two identical copies of DNA from a single original DNA molecule. This process occurs in all living organisms. It beings at specific locations within the genome called origins of replication. These origins of replication are areas of high T-A base pairing. This is important because there are less hydrogen bonds between the A-T bases so the strand is easier to break at those points. This is known as initiation and at this point the DNA strand is unwound by proteins and enzymes known as helicases, which expose the two strands and result in replication forks that are bi-directional from the origin. Topoisomerases are enzymes used to temporarily break the strands of DNA to relieve tension. These two strands then serve as a template for the leading and lagging strands which will be created as a DNA polymerase will match complementary nucleotides to the templates. DNA is always synthesized in the 5′ to 3′ direction and because at the replication fork the template strands are oriented in opposite directions the leading strand is the strand of nascent DNA which is being synthesized in the same direction as the growing replication fork and replication is continuous in the 5′ to 3′ direction. Within the lagging strand the nascent DNA being synthesized is in the opposite direction, and because of this replication lags and is fragile. Primase is an enzyme that synthesizes a short RNA primer with a free 3′ OH group which is then elongated by a DNA polymerase. The leading strand only receives one RNA primer, while the lagging strand receives several. The leading strand is continuously extended by a DNA polymerase, while the lagging strand is extended discontinuously from the multiple primers forming Okazaki fragments. DNA clamp proteins form a sliding clamp around the DNA, this allows the DNA polymerase to maintain constant contact with the template strands, and enhancing processivity. Once DNA polymerase reaches the end of the template strands and runs into double-strand DNA the sliding clamp protein complex undergoes a conformational change and releases the DNA polymerase. RNase then removes the RNA primers and is replaced by DNA ligase which joins together the multiple parts of the DNA.
DNA replication occurs at multiple points within the chromosome of an organism and because of the linear nature of chromosomes these replication forks are unable to reach the terminal ends and as a consequence a small amount of DNA is lost each replication cycle. Telomeres are regions of repetitive DNA close to the ends of the chromosomes that help mitigate the loss of genomic material during replication. These telomeres are finite and thus each cell has a terminal number of replications. This is otherwise known as the Hayflick limit. When DNA is passed down the germ cell line telomerase is an enzyme that extends the repetitive sequences of the telomere region. Telomerase can become mistakenly up-regulated in somatic cells, which can sometimes lead to cancer.
This is the first release of a 3 part series of articles dedicated to the Central Dogma of life. This article covered what RNA, DNA and DNA replication are.