RNA biology has won two consecutive Nobel Prizes in 2023 and 2024. Along with other groundbreaking discoveries, these Nobel Prize-winning advancements in RNA biology have significantly impacted the field of molecular biology and continue to challenge some of our central ideas about life and gene regulation. One of the best examples supporting this notion is the influence of RNA biology on the central dogma of molecular biology. Here, I expand on how RNA has reshaped one of the key concepts in the field.
What is the Original Concept of the Central Dogma?
The original concept of the central dogma of molecular biology was proposed by Francis Crick in 1958 and further elaborated in 1970. It outlines the flow of genetic information within a biological system, describing how information stored in DNA is used to synthesize RNA, which then directs the synthesis of proteins. The central dogma states: DNA to RNA to protein. The flow is intended to be unidirectional. DNA serves as a template for its own replication, ensuring the transfer of genetic information during cell division. Next, RNA is produced through the transcription of DNA. Finally, proteins are generated during the translation of the RNA transcript into an amino acid sequence.
The central dogma specifically emphasizes that once information is in the form of protein, it cannot be transferred back to either RNA or DNA. This rule laid the foundation for understanding gene expression and protein synthesis.
Reverse Transcription: Challenging the Flow of Information
The discovery of reverse transcription was the first major breakthrough that redefined the central dogma. This phenomenon, first observed in retroviruses, demonstrated that RNA could serve as a template for DNA synthesis, effectively reversing the traditional flow of genetic information. The implications were profound: this mechanism enabled RNA viruses to integrate into host genomes, revealing a bidirectional flow of information between nucleic acids. Additionally, reverse transcription plays a significant role in genomic evolution and gene structure variation, including the phenomenon of intron loss. It serves as a crucial mechanism for intron loss by introducing cDNA copies of intronless mRNAs into the genome, leading to structural changes in genes.
RNA Modifications and Editing: Expanding Genetic Versatility
RNA modifications are another discovery that fundamentally altered our understanding of gene expression. RNA modifications involve direct changes to RNA sequences post-transcriptionally, resulting in RNA molecules that differ from their DNA templates. The best-studied form of RNA modification is adenosine-to-inosine (A-to-I) editing which alter codon specificity and can modulate protein function. These modification events can create new splice sites, alter protein-coding sequences, or change regulatory elements in untranslated regions.
RNA editing in trypanosomatid mitochondria is a unique and essential post-transcriptional modification process that alters the RNA sequences transcribed from mitochondrial DNA. This mechanism involves the insertion and deletion of uridine (U) nucleotides, significantly modifying the coding sequences and leading to the production of functional mRNAs that can be translated into proteins. In some cases, up to 60% of the mRNA sequence can be altered from the original transcript, indicating that the exact information from the DNA is not necessarily reflected at the protein level. This challenges the simplistic view of the central dogma at its core.
What About Non-Coding RNAs?
The discovery of non-coding RNAs, such as miRNAs and lncRNAs, has revealed layers of gene regulation that occur independently of protein production. The star RNA today is the miRNA. miRNAs are another case where the flow of information is interrupted and controlled by RNA itself. MicroRNAs (miRNAs) are small, non-coding RNA molecules, typically about 20-24 nucleotides long, that play a critical role in regulating gene expression at the post-transcriptional level. miRNAs primarily function by binding to complementary sequences on target messenger RNAs (mRNAs), leading to their degradation or inhibiting their translation into proteins. This regulatory mechanism is essential for controlling various cellular processes, including development, differentiation, proliferation, and apoptosis.
Thus, while the central dogma’s core principle—that genetic information can be transcribed into RNA and translated into proteins—still holds, it is now recognized as a “central framework” rather than a strict rule. Reverse transcription and RNA editing are prime examples of how RNA biology has reshaped our understanding of the central dogma. They illustrate RNA’s versatility as a carrier of genetic information and a regulator of gene expression, challenging the once simplistic view of DNA-RNA-protein. As new RNA-based mechanisms continue to emerge, our understanding of molecular biology remains ever-evolving. This sparks further scientific and philosophical discussions about our understanding of evolution and the modern synthesis. In my opinion, this also challenges reductionists who seek to impose strict rules and “equations” to describe biological phenomena.
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