Billions of years ago, a genetic component known as LINE-1 emerged as a genome colonizer in primitive lifeforms. This element, using a copy-and-paste mechanism, replicated itself across various genomes. Over time, it became a significant part of the eukaryotic organisms’ genetic makeup, including humans, where it constitutes about one-third of the human genome. Previously considered junk DNA, LINE-1 is now recognized for its substantial impact on our genetic code.Â
Scientists from Rockefeller University, in collaboration with various academic and industry groups, have achieved a breakthrough by determining the high-resolution core structure of a key protein, ORF2p, associated with LINE-1. This discovery, published in Nature, offers new insights into the disease-causing mechanisms of LINE-1. The study highlights the potential for developing novel therapies to combat diseases such as cancer, autoimmune disorders, neurodegeneration, and other aging-related diseases.Â
LINE-1 is a retrotransposon, a type of mobile genetic code that can translate RNA back into DNA and insert itself into different genome locations. It shares an evolutionary connection with group II introns, ancient mobile elements dating back about 2.5 billion years. LINE-1 has evolved alongside its host organisms for billions of years, often inserting itself into their genomes.Â
ORF2p is a multifunctional protein essential for LINE-1’s replication and insertion activities. Using techniques like X-ray crystallography and cryo-EM, researchers discovered novel domains within ORF2p that facilitate LINE-1’s replication. This protein’s unique structure allows it to handle various tasks, from replication to insertion, unlike most viruses that require multiple proteins for these functions.Â
When activated, LINE-1 can mimic viral behavior, triggering the innate immune system and potentially contributing to autoimmune diseases and other conditions. The study also explored the interactions between LINE-1 and the cGAS/STING antiviral pathway, which can lead to inflammation similar to viral infections.Â
The researchers aim to further understand the newly discovered core domains of ORF2p and their functions. They also plan to explore clinical applications of their findings, particularly in designing targeted therapies for LINE-1 related diseases. The study underscores the potential of integrating diverse data and expertise to address fundamental biomedical questions.Â
Journal Reference Â
Baldwin, E. T., van Eeuwen, T., Hoyos, D., Zalevsky, A., Tchesnokov, E. P., Sánchez, R., … Taylor, M. S. (2023). Structures, functions, and adaptations of the human LINE-1 ORF2 protein. Retrieved from https://www.nature.com/articles/s41586-023-06947-zÂ
