The Long Interspersed Element-1 (LINE-1) retrotransposon is an ‘ancient genetic parasite’ that has written around one third of the human genome through a ‘copy-and-paste’ mechanism and serves as an active source of genetic diversity and human disease.
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The human genome contains approximately half a million copies of LINE-1. Image credit: Baldwin et al., doi: 10.1038/s41586-023-06947-z.
The LINE-1 retrotransposon, one of the most common elements in human DNA, is a major part of the ‘dark genome,’ the poorly understood genetic material that doesn’t provide blueprints for any of the proteins that human bodies use.
Usually dormant in healthy cells, in disease, LINE-1 can break free and make proteins, including one called the LINE-1 ORF2 protein (LINE-1 ORF2p) that attempts to add new mutation-causing copies of LINE-1 back into our DNA.
Increased activity of the LINE-1 elements appears to be a common driver of autoimmunity, cancer, and other diseases.
Detailed knowledge of LINE-1, along with LINE-1 RNA and LINE-1 ORF2p, may enable the discovery or creation of drugs that bind to one or more of these molecules and stop them from damaging the body.
“Retrotransposons are often referred to as ‘jumping genes’ that insert themselves into our chromosomes with a copy-and-paste mechanism,” said University of Alberta’s Professor Matthias Götte.
“We discovered the essential steps in this process, which could then lead us to ways to inhibit the enzyme and eventually treat those diseases.”
The team was able to capture the first high-resolution images of LINE-1 ORF2p and reveal its structural details.
“As the paper explains, these analyses reveal the intricate workings of the molecular machine that has written nearly half of the human genome,” said Rutgers University’s Professor Eddy Arnold.
“The healthy body has mechanisms to repress these, but in disease states like cancers, these systems do not work properly.”
“Through this amazing team effort, we now have a detailed understanding of how LINE-1 ORF2p works, which existing drugs do and do not work, and why.”
“We also made major advances in our understanding of the evolution of these elements and how this may relate to viruses.”
“All of this was only possible because of the highly collaborative and multidisciplinary team.”
“A key reason that we were able to make these advances is that we had an incredibly talented team with deep knowledge of structural biology and biochemistry of both mobile elements and viruses,” said Dr. Martin Taylor, a researcher at Massachusetts General Hospital and Harvard Medical School.
“These molecules have an impact on us that goes way beyond diseases,” said Rutgers University’s Professor Francesc Xavier Ruiz.
“For example, researchers have found out that insertion of these ‘junk’ DNAs in the middle of the genes coding for the tail in hominids may explain why we no longer have tails.”
“Indeed, the biological functions of the dark genome remain largely unknown, but clearly, activities there can shape who we are,” Professor Arnold said.
“It was a large team effort with world-class structural biologists,” Professor Götte said.
“Effective treatments for important human diseases can only be developed with a very strong scientific foundation.”
A paper describing this research was published December 14 in the journal Nature.
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E.T. Baldwin et al. Structures, functions, and adaptations of the human LINE-1 ORF2 protein. Nature, published online December 14, 2023; doi: 10.1038/s41586-023-06947-z
