The Central Dogma of Molecular Biology and Its Limitations

Post-Translational Modifications and Protein Function

Post-translational modifications (PTMs) are critical biochemical processes that occur after a protein has been synthesized, where the protein's structure and function are altered by the addition or removal of functional groups or the cleavage of peptide bonds. These modifications can include phosphorylation, glycosylation, ubiquitination, and more, which can affect protein stability, localization, activity, and interactions with other molecules. PTMs add a layer of complexity to the central dogma of molecular biology, which traditionally describes the flow of genetic information from DNA to RNA to protein, by showing that the final protein product can be extensively modified and regulated after synthesis.

Inteins and Protein Splicing

Inteins are protein sequences that are able to catalyze their own excision from a host protein and subsequently join the remaining portions, known as exteins, to form a functional protein. This process, called protein splicing, is a form of post-translational modification. Inteins sometimes contain a homing endonuclease or a maturase domain, which can facilitate horizontal gene transfer by inserting or correcting intein sequences in new locations within the genome. This activity demonstrates a direct role for proteins in the modification of genetic material, providing an exception to the central dogma's principle that information flows from nucleic acids to proteins but not in reverse.

DNA Methylation and Gene Expression

DNA methylation involves the addition of methyl groups to the cytosine or adenine nucleotides of DNA, often leading to changes in gene expression. This epigenetic mechanism is catalyzed by enzymes known as DNA methyltransferases and can result in the silencing of genes. Methylation patterns can be heritable and play a role in development, genomic imprinting, and the suppression of transposable elements. While DNA methylation does not change the DNA sequence itself, it does alter how cells use that sequence, thereby influencing the central dogma by controlling the potential for gene expression prior to transcription.

Prions and Protein-Based Inheritance

Prions are infectious agents composed solely of protein that can induce misfolding in normal, cellular prion proteins, leading to a cascade of misfolding and aggregation. This process can result in diseases such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in cattle. Prions challenge the central dogma by demonstrating a form of inheritance based on protein conformation rather than nucleic acid sequence. While prions do not encode genetic information or replicate in the manner of nucleic acids, they represent a non-traditional means of transmitting biological information, which can have profound effects on cellular function.

Reevaluating the Central Dogma

The concept of natural genetic engineering, introduced by molecular biologist James A. Shapiro, posits that cells are capable of more sophisticated genetic manipulation than previously thought, including the ability to restructure their own genomes. This concept, along with the examples of post-translational modifications, inteins, DNA methylation, and prions, suggests that the central dogma, while useful, may not fully capture the complexity of genetic information flow and regulation. The central dogma, originally proposed by Francis Crick, is not incorrect but rather incomplete, as it does not account for these dynamic interactions between proteins and nucleic acids that can influence the phenotype beyond the direct sequence of DNA and RNA.