Revealing How an Ancient Genetic Invader (LINE-1) Inhabits Our DNA

LINE-1 is a retrotransposon associated with disease and aging. Rockefeller scientists and collaborators have uncloaked the core of its key protein, pointing the way towards therapeutic targets.

Billions of years ago, as primitive lifeforms were becoming more complex, a selfish genetic component became a sort of genome colonizer. Using a copy-and-paste mechanism, this pernicious bit of code replicated and inserted itself again and again into a variety of genomes. Over time, all eukaryotic organisms, including humans, inherited the code. In fact, this ancient genetic element wrote about one-third of the human genome—and was considered junk DNA until relatively recently. This genetic component is known as LINE-1 (long interspersed nuclear element 1) (L1), and its aggressive intrusion into the genome can wreak havoc, leading to disease-causing mutations. A key protein called ORF2p enables its success—meaning understanding ORF2p’s structure and mechanics could illuminate new potential therapeutic targets for a variety of diseases. ORF2p encodes the endonuclease and reverse transcriptase activities required for L1 retrotransposition. Now, in collaboration with more than a dozen academic and industry groups, Rockefeller University scientists have rendered the protein’s core structure in high-resolution for the first time, revealing a host of new insights about LINE-1’s key disease-causing mechanisms. The results were published on December 14, 2023 in Nature. The article is titled “Structures, Functions, and Adaptations of the Human LINE-1 ORF2 Protein.”

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