The Central Dogma of Molecular Biology

The central dogma of molecular biology sounds, in theory, quite simple. It states that the flow of genetic information goes from DNA to RNA to proteins; it also illustrates that DNA is replicated to ensure each new cell after the division has a complete set of genes. Francis Crick first proposed and published the central dogma in 1970, 17 years after discovering DNA with James Watson. The general idea of the doctrine has remained largely unchanged, however, the molecular mechanisms by which these steps are achieved have been illuminated.

Figure 1: Flow of genetic information between DNA, RNA, and protein. Genome Research Limited. 2021.

DNA Replication

Before a cell divides into two identical cells, the genome must be replicated to be distributed in each cell. DNA replication is a complex, multi-step process involving several different enzymes and checkpoint molecules. The steps involved are divided into three major categories: initiation, elongation, and termination. It is first important to understand the structure of DNA which is a double helix with a sugar-phosphate backbone, meaning each segment of DNA has two complementary strands bound together by hydrogen bonds between four types of nucleotides: adenine, guanine, thymine, and cytosine. An adenine nucleotide in one strand binds to thymine in the complementary strand with two hydrogen bonds holding them together while cytosine in one strand binds to the complementary guanine with three hydrogen bonds. DNA also has directionality with one end of a strand being the 3’ (three prime) end and the other designated as the 5’ (five prime) end; the 3’ end of one strand is across from the 5’ end of the complementary strand. Replication always occurs in the 5’ to 3’ direction and is semi-conservative so that each “parental strand serves as a template for the synthesis of a new complementary daughter strand,” (Cooper, 2000, Ch. 5).

Figure 2: DNA Structure. Wikimedia Foundation, Inc. 2010.

During the initiation phase, initiator proteins bind to specific segments of DNA known as replication origins. Afterward, an enzyme known as DNA helicase unzips the double helix by breaking the hydrogen bonds so that the two strands are separated, creating replication forks (Alberts, Johnson, et al., 2002, Ch. 5). During the elongation phase, DNA polymerase adds new complementary nucleotides to the template strand in order to synthesize the new strand. DNA polymerase adds the nucleotides in the 5’ to 3’ direction so that there is both a leading and a lagging strand, and the enzyme can only add nucleotides to a strand if a primer enzyme—primase—has created a short “RNA polynucleotide strand complementary to the template DNA strand” known as a primer (Bio.libreTexts, 2021, p. 9276). The leading strand is able to be synthesized continuously and only needs one RNA primer, whereas the lagging strand is synthesized in short segments known as Okazaki fragments which each have their own RNA primer. The lagging strand is replicated in such a way as the direction of synthesis is opposite to the direction that the replication fork grows. Finally, during termination, the RNA primers are replaced with DNA nucleotides by a group of enzymes known as FEN1 and RNase H, and any gaps in the sugar-phosphate and the Okazaki fragments are joined together by DNA ligase.

Figure 3: Replication of leading and lagging strands. Genome Research Limited. 2021.

Transcription

Transcription is the process by which genetic information encoded in DNA is transcribed into single-stranded RNA—the form of genetic information that is later translated into proteins. Due to the fact that DNA is double-stranded, only one strand is copied into RNA, which is known as the template or noncoding strand. The DNA strand that is complementary to the template is referred to as the non-template or coding strand as its sequence will be identical to the RNA strand transcribed from the template; the only exception is that instead of thymine, RNA uses the nucleotide base uracil. The steps for transcription are the same as replication: initiation, elongation, and termination. Initiation beings when RNA polymerase (RNA pol) binds to the template DNA strand at a promoter region and starts to catalyze the production of complementary RNA (Clancy, 2008, p. 1). The enzyme “reads” the DNA sequence and creates a sequence of complementary RNA. Next, elongation occurs as more RNA nucleotides are added to the growing single-stranded RNA strand. When RNA pol comes across an adenine molecule, the enzyme adds uracil instead of thymine which is added by DNA polymerase in replication. It also is important to note that, unlike replication which results in two semi-conservative double-stranded DNA sequences, transcription results in a single RNA strand. Finally, termination occurs when RNA polymerase encounters a termination sequence in the gene that is being transcribed. Similar to a promoter sequence that allows transcription to start, a termination sequence causes the RNA pol to detach from the DNA (Carter, 2022, p. 1).

Figure 4: The process of transcription. Genome Research Limited. 2021.

Post transcription, there are edits that need to be made to the RNA strand to create a messenger RNA (mRNA) that is ready for translation. The mRNA strand must be protected from degradation long enough to be translated into proteins and this is achieved by capping the 5’ end and adding a tail of “approximately 200 adenine (A) residues, called the poly-A tail,” (Carter, 2022, p. 1). Both of these modifications delay the degradation of mRNA molecules in the cytoplasm. Splicing is the final post-transcriptional modification made to mRNA. mRNA strands are made of segments known as introns and exons, however, only exons are expressed while introns are spliced out of the mRNA strand by a spliceosome enzyme thereby ensuring that only exons are translated.

Translation

Translation is the process by which mRNA is “read” and translated into proteins. The cellular machinery that "reads" and adds amino acids to in a chain-like fashion are ribosomes and transfer RNAs (tRNAs). Ribosomes have both a small subunit that binds to the mRNA template and a large subunit that binds to the tRNAs that “bring amino acids to the growing chain of the polypeptide,” (Fowler, Roush, et al., 2021). These tRNAs bind amino acids on one end and bind to the mRNA at the other. The translation of mRNA strands to proteins is accomplished through the use of the genetic code. Three nucleotides of mRNA—called a triplet or a codon—translate directly to amino acid; for example, the combination of adenine, uracil, and guanine, (AUG) in that order would translate to the amino acid methionine (Met) which is the codon that sets the reading frame and universally starts translation at the 5’ end of the mRNA.

As with replication and transcription, translation can be divided into three steps: initiation, elongation, and termination. During initiation, mRNA binds to the small ribosomal subunit and an “initiator tRNA interacts with the AUG start codon, and links to a special form of the amino acid methionine that is typically removed from the polypeptide after translation is complete,” (Fowler, Roush, et al., 2021). Elongation involves the large ribosomal subunit which has three different binding sites for the tRNAs. The A site binds to incoming tRNAs that have been bound to an amino acid but have yet to add it to the growing peptide while the P site holds tRNAs with a corresponding amino acid that have already been bonded to the polypeptide but are still associated with the tRNA; finally, the E site the release of tRNAs that have already transferred their amino acids occurs (Fowler, Roush, et al., 2021). Termination occurs the translation mechanism encounters a stop codon, UAA, UAG, or UGA which causes the polypeptide to be released.

Figure 5: The process of translation. Genome Research Limited. 2021.

The central dogma of molecular biology states that the flow of genetic information goes from DNA to RNA to proteins, however, the reality of how that happens is much more complex. DNA replication, transcription, and translation take place every single day to ensure our cells—both old and new—function properly and have a full and error-free genome.

Bibliographic References

Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Molecular Biology of the Cell, Fourth Edition (4th ed.). Garland Science. https://www.ncbi.nlm.nih.gov/books/NBK21054/ Carter, S. (2022). Transcription. Bio.LibreTexts. https://bio.libretexts.org/@go/page/35713 Clancy, S. (2008) DNA Transcription. Nature Education. https://www.nature.com/scitable/topicpage/dna-transcription-426/ Cooper, G. (2000). The Cell: A Molecular Approach (2nd ed.). Sinauer Associates Inc. https://www.ncbi.nlm.nih.gov/books/NBK9839/ Fowler S., Roush, R., Wise, J. (2021) Translation. Bio.LibreTexts. https://bio.libretexts.org/@go/page/7025 Unknown. (2021). DNA Replication in Eukaryotes. Bio.LibreTexts.

https://bio.libretexts.org/@go/page/9276

Visual Sources

Cover Image: Unknown. (2015). DNA. Shuttershock. [Illustration]. Image retrieved from https://www.sciencealert.com/the-breakthrough-technology-that-lets-scientists-edit-dna-just-got-a-whole-lot-cheaper-and-easier.

Figure 1: Unknown. (2021). Flow of genetic information between DNA, RNA, and protein. Genome Research Limited. [Illustration]. Image retrieved from https://www.yourgenome.org/facts/what-is-the-central-dogma/ Figure 2: Unknown. (2010). DNA Structure. Wikimedia Foundation, Inc. [Illustration]. Image retrieved from https://commons.wikimedia.org/wiki/File:DNA_structure_and_bases_color_FR.svg Figure 3: Unknown. (2021). Replication of leading and lagging strands. Genome Research Limited. [Illustration] Image retrieved from https://www.zmescience.com/medicine/genetic/dna-replication-steps-43264/ Figure 4: Unknown. (2021). The process of transcription. Genome Research Limited. [Illustration]. Image retrieved from https://www.yourgenome.org/facts/what-is-gene-expression/ Figure 5: Unknown. (2021).The process of translation. Genome Research Limited. [Illustration]. Image retrieved from https://www.yourgenome.org/facts/what-is-gene-expression/