Study reveals details of process driving evolution and major diseases

(Press-News.org) Viruses are known to use the genetic machinery of the human cells they invade to make copies of themselves. As part of the process, viruses leave behind remnants throughout the genetic material (genomes) of humans. The virus-like insertions, called “transposable elements,” are snippets of genetic material even simpler than viruses that also use host cell machinery to replicate.

Nearly all these inserted elements have been silenced by our cells’ defense mechanisms over time, but a few, nicknamed “jumping genes,” can still move around the human genome like viruses. Just one, called long interspersed nuclear element 1 (LINE-1), can still move by itself.

As an element type that behaves like the retrovirus HIV, the LINE-1 “retrotransposon” is first copied into a molecule of RNA, the genetic material that partners with DNA, and then the RNA LINE-1 copy is converted back into DNA in a new place in the genome. In this way, retrotransposons add code to the human genome every time they move, which explains why 500,000 LINE-1 repeats now represent a “staggering” 20 percent of the human genome. These repeats drive genome evolution, but can also cause neurological diseases, cancer, and aging when LINE-1 randomly jumps into essential genes, or triggers an immune response like a virus to cause inflammation. 

To copy itself, however, LINE-1 must enter each cell’s nucleus, the inner barrier that houses DNA. Now a new study, published online May 2 in the journal Science Advances, reveals that LINE-1 binds to cellular DNA during the brief periods when nuclei break open as cells continually divide in two, creating replacements to keep tissues viable as we age. The research team found that LINE-1 RNA takes advantage of these moments, assembling into clusters with one of the two proteins it encodes, ORF1p, to hold tightly to DNA until the nucleus reforms after cell division.

Led by researchers at NYU Langone Health and the Munich Gene Center at Ludwig-Maximilians-Universität (LMU) München in Germany, the work revealed specifically that LINE-1 can only bind to DNA when ORF1p – which can bind to RNA, DNA, and itself in linked copies called multimers – accumulates into clusters of hundreds of molecules called condensates. As more ORF1p molecules build up, they eventually envelop the LINE-1 RNA, which makes more binding sites available for the entire cluster to attach to DNA. 

"Our study provides crucial insight into how a genetic element that has come to make up a large part of human DNA can successfully invade the nucleus to copy itself, said Liam J. Holt, PhD., associate professor in the Department of Biochemistry and Molecular Pharmacology, and the Institute for Systems Genetics, at NYU Grossman School of Medicine. “These findings on the precise mechanisms behind LINE-1 insertion lay the foundations for the design of future therapies to prevent LINE-1 replication.”

The work also suggests that the LINE-1 condensate acts as a delivery vehicle to bring its RNA into proximity of the right sequences (rich in the DNA bases adenine and thymine) on DNA where the retrotransposon tends to insert, say the study authors. Packaged in its condensates, LINE-1 is thought to evade mechanisms that exclude large particles from the nucleus during mitosis as a cellular defense against viruses.

“LINE-1 condensates have a remarkable feature in that their DNA binding ability emerges only when the ratio of ORF1p copies to RNA is high enough in the condensates,” added Dr. Holt. “Moving forward we will be looking to see if other condensates undergo functional changes as the ratios between their components change.”

Along with Dr. Holt, the first study authors were graduate student Farida Ettefa at NYU Grossman School of Medicine and its Institutes for Systems Genetics; and Sarah Zernia of Gene Center Munich at Ludwig-Maximilians-Universität (LMU) München in Germany. Also study authors were Cas Koeman, Joëlle Deplazes-Lauber, Marvin Freitag, and co-senior author Johannes Stigler from Ludwig-Maximilians-Universität München. The study was supported by the LMU-NYU Research Cooperation Program.

About NYU Langone Health
NYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked NYU Langone No. 1 out of 115 comprehensive academic medical centers across the nation for three years in a row, and U.S. News & World Report recently placed nine of its clinical specialties among the top five in the nation. NYU Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. With $14.2 billion in revenue this year, the system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.

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