Syed Masood
Nature 1953, Watson and Crick publish “Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid,” winning the race with researchers around the globe to first publish the structure of DNA, the illustrious double helix. The seminal work of Dr. Rosalind Franklin in X-ray crystallography contributed significantly to this discovery, which led James Watson, Francis Crick, and Maurice Wilkins to receive the 1962 Nobel Prize in Physiology or Medicine.
Beyond DNA, Francis Crick coined the central dogma of molecular biology, “DNA makes RNA and RNA makes protein.” Today we know these processes as Transcription (DNA to RNA) and Translation (RNA to Protein). These processes essentially give cells life. Just roughly 20,000 genes in a sequence of A, T, G, C give rise to a vast array of proteins that carry out functions essential for life. These include transports like ion channels and aquaporins, glycolytic enzymes like GAPDH, cytoskeletal proteins like beta-actin, and transcription factors like NF-kB and Nrf2. Transcription and Translation thus are central modes by which cells exhibit life itself.
Today, we know that these processes are tightly regulated and highly conserved. Yet, we also know that both processes can be altered in many disease states. The classic and quintessential example is that of cancer. The decreased expression of tumor-suppressor genes and the increased expression of cancer-promoting genes, also called oncogenes, represent the abhorrent hijacking of the processes of Translation and Transcription by cancer cells.
On October 7th, 2024, the 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros, and Gary Ruvkun for their discovery of microRNAs and their roles in post-transcriptional gene regulation.
In the early days of genetics, during the 1960s, the predominant idea was that transcription factors were the predominant method of gene regulation. Transcription factors are proteins that bind to specific regions of the DNA, controlling the flow of genetic information to be transcribed into RNA. However, this understanding was challenged during the late 1980s when Ambros and Ruvkun, two postdoctoral researchers in the lab of the Robert Hortvitz (winner of the 2002 Nobel Prize in Physiology or Medicine for his “discoveries of concerning genetic regulation of organ development and programmed cell death”), started investigating developmental genes in C elegans.
During this investigation, Ambros and Ruvkun focused on two genes lin-4 and lin-14, where lin-4 showed a negative regulation of lin-14, though the mechanism remained unknown. It wasn’t until Ambros established his own laboratory that he found that the lin-4 gene encoded a short RNA molecule that is not translated into a protein- a microRNA. Ruvkun, in his lab, showed that the lin-4 regulation of lin-14 occurred after it had already been transcribed. Furthermore, the two showed that the RNA sequence of lin-4 was complementary to that of the RNA sequence of lin-14.
Today, we know quite a bit more about microRNAs and their ability for post-transcriptional regulation. MicroRNAs are incredibly short, about 21-23 nucleotides long, single-stranded, non-coding RNAs. Their main function is to silence encoding messenger RNA (mRNA) by either degrading the mRNA or by inhibiting its translation into proteins. In the human genome, over 500 microRNA encoding genes have been found.
In just over 70 years, our understanding of gene regulation has advanced from simply transcription and translation during the Watson and Crick era to a more complex and nuanced understanding. MicroRNAs represent an exciting new frontier in understanding the complexities of the human genome: how genes are expressed, regulated, and hijacked. Modern approaches use microRNAs as both markers of disease and toxicological exposures, as well as interventional approaches for gene therapy. Indeed, the work by Ambros and Ruvkun is foundational in providing evidence and discovery of how microRNAs post-transcriptionally regulate gene expression.
Peer Editor: Luvna Dhawka