by Rockefeller University

Credit: CC0 Public Domain

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 inherited the code—including us. 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, 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.

Now, in collaboration with more than a dozen academic and industry groups, Rockefeller 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 in Nature.

"The work will facilitate rational drug design targeting LINE-1 and may lead to novel therapies and strategies to combat cancer, autoimmune disease, neurodegeneration, and other diseases of aging," says senior author John LaCava, a research associate professor at The Rockefeller University.

Evolutionary mates

LINE-1 is a retrotransposon, a kind of mobile genetic code that translates RNA back into DNA while replicating and writing itself into different places throughout an organism's genome. There are different kinds of retrotransposons, including endogenous retroviruses (ERVs), which resemble HIV and Hepatitis B (HBV).

LINE-1's origin is unclear, but it has an evolutionary connection to group II introns, a class of ancient mobile elements dating back about 2.5 billion years. Retrotransposons like LINE-1 have been evolving with their host organisms for 1 to 2 billion years.

"It's an ongoing battle between LINE-1 trying to insert itself and the host protecting its own genome," says co-first author Trevor van Eeuwen, a postdoctoral fellow in Rockefeller's Laboratory of Cellular and Structural Biology.

Millions of genetic fragments derived from LINE-1 are found in our cells. The vast majority are inactive evolutionary relics, evidence of failed attempts to hijack the replication machinery. But about 100 LINE-1s are operational—and usually not helpful. One protein produced by LINE-1, known as ORF1p, is churned out by cancer cells, as a recent study by LaCava, Michael P. Rout, and their collaborators described.

LaCava and Martin Taylor, of Massachusetts General Hospital and Harvard Medical School, have collaboratively studied LINE-1 and its proteins for more than a decade, but because ORF2p expresses so lowly and infrequently, it has remained poorly understood. "LINE-1 has been so difficult to study because it has very weird features," LaCava says.

"For instance, it has an unusual replication cycle and the ORF2p protein that no one's been able to capture. But Marty and I eventually reached a place where our research on it was mature enough so that we could begin to study its structure."

Taylor made key advancements in purifying the full-length ORF2p as well as a shorter "core" version that facilitates L1 replication; these advances facilitated the breakthroughs that followed.

More information: Eric T. Baldwin et al, Structures, functions, and adaptations of the human LINE-1 ORF2 protein, Nature (2023). DOI: 10.1038/s41586-023-06947-z

Journal information: Nature 

Provided by Rockefeller University