Conducted by scientists from the University of Michigan Medical School and Louisiana State University, the study is the first to show in mammalian cells that some human LINE-1, or L1, elements can jump to chromosomes with broken strands of DNA, slip into the break and repair the damage.
"Transposable L1 elements make up 17 percent of our DNA, but very little is known about them," says John V. Moran, Ph.D., an assistant professor of human genetics and internal medicine in the U-M Medical School, who developed the first assay to identify mobile L1s in the human and mouse genomes. "Until now, everyone thought L1s were just intracellular parasites in our DNA - leftovers from the distant evolutionary past. The big question in the field is: Are they still there because we can't get rid of them or do they have a function?"
L1s "reproduce" by using RNA and a process called reverse transcription to make complementary DNA copies of themselves, which can jump into other DNA sequences. Normally, L1s use an enzyme called endonuclease to cut the genetic DNA and create a space, so they can plug themselves into the genome.
"We knew about the endonuclease pathway," says Tammy A. Morrish, a U-M graduate student in human genetics and first author of the paper. "But we didn't know there was another mechanism that didn't require endonuclease, or that L1s could jump into existing breaks in DNA."
Morrish tested human L1s' ability to repair DNA breaks in several normal and DNA-repair mutant cell lines derived from Chinese hamster ovary cells. Other researchers had demonstrated the ability of human L1s to repair DNA breaks in yeast cells, but Morrish is the first to show the effect can occur in mammalian cells.
Since DNA damage may lead to cell death unless it is repaired, the existence of an alternate repair pathway could be a good thing for the host cell. The question is, what's in it for the L1?
"This study brings up the question of whether L1s are just taking advantage of DNA breaks to plug themselves into these sites or are they are being used by the host cell to mediate the repair," says Moran. "From the L1s' point of view, this gives it an alternate way of integrating into the DNA."
Because L1s are so ancient and because they sometimes carry segments of genes with them when they jump to a new location, Moran believes they have played an important role in human evolution by increasing genetic diversity. He is one of only a few scientists to study L1s in the human genome.
"We have more transposable L1s in the human genome than any other species, but we know the least about where and how they move in humans," says Moran. "We are here today either because of, or in spite of, L1s."
In future research, Moran's research team will examine whether it is possible to direct L1s to repair specific breaks in DNA, whether L1s can be used as vectors to deliver genetic material to specific DNA locations, and the impact of an L1 insertion on genes.
U-M researchers in the study were supported by the William M. Keck Foundation and the National Institutes of Health. Nicholas Gilbert, Ph.D., a U-M post-doctoral fellow in human genetics, collaborated in the study. Other collaborators included Mark A. Batzer, Jeremy S. Myers, and Bethaney J. Vincent from Louisiana State University; Thomas D. Stamato from Lankenau Institute for Medical Research in Wynnewood, Penn.; and Guillermo E. Taccioli from Boston University's School of Medicine.
Nature Genetics: June 2002, 31:2, 159-165.
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