Parasite DNA sequence hijacks cell’s own repair machinery

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Like its viral cousins, a slightly parasitic DNA sequence called a retrotransposon has been discovered that borrows the cell’s own machinery to achieve its target.

In a new piece that appeared online Wednesday in the magazine Naturea Duke University research team has determined that retrotransposons hijack a little-known part of a cell’s DNA repair function to close itself into a ring-like shape and then create a matching double chain. .

This finding reverses the conventional wisdom of 40 years that these rings are just a useless byproduct of bad gene duplication. It could also provide new insights into cancer, viral infections and immune responses.

Retrotransposons are fragments of DNA about 7,000 characters long that copy and paste themselves into different parts of the genomes of both plants and animals. In this way, they play a role in rewriting DNA and regulating how the cell uses its genes.

Retrotransposons are believed to be behind so many variations and innovations in genes that drive evolution and are inherited from both parents.

Many studies have suggested that these extra-chromosomal DNA rings are somehow involved in the development and progression of cancer in part because they are known to contain oncogenes in the DNA sequence. of them. The HIV retrovirus, which causes AIDS, is also known to form circular DNA.

“I think these factors are at the root of the genomic dynamics,” said Zhao Zhang (ZZ), an assistant professor of pharmacology and cancer biology and a Duke Science & Technology scholar. evolution of animals and even affect our daily lives. «But we’re still in the process of appreciating their functionality.»

Retrotransposons are fairly common – they make up about 40% of the human genome and more than 75% of the maize genome – but how and where they replicate themselves has always been a mystery.

Zhang holds a thick textbook on retroviruses that he referenced for this study. The books say that the circular sequences are «created by recombination of the two ends of linear DNA, and are just a dead end, a byproduct of replication failure,» he said.

In previous work with fruit fly eggs, Zhang’s team determined that inherited retrotransposons use egg-assisted ‘nurse cells’ as factories to produce multiple copies of themselves, which are then distributed distributed throughout the genome in the developing egg of the fly. This model system allows researchers to zoom in even further to learn more about retrotransposons.

In their latest study, they unexpectedly discovered that most of the newly added retrotransposons were in this circular form rather than integrated into the host genome. They then conducted a series of experiments that knocked out each cell’s DNA repair mechanism to figure out how and where the circles were formed.

Answer: A little-studied DNA repair mechanism called alternative end-to-end DNA repair, or alt-EJ for short, helps repair double-strand breaks. Retrotransposon sequences are using this part of the host’s repair machinery to stitch the ends of their single-stranded DNA together and then use its DNA synthesis to create the matching double-strand . For a good measure, the researchers confirmed that this is also the process that occurs in human cells.

So retrotransposons are not a sloppy accident; they’re actually hijacking a little bit of the cell’s machinery to produce more of itself, like viruses.

“Our discovery really inverted the textbook model,” says Zhang. “We have shown that the recombination event proposed by the textbook is not important for the formation of the rings,” said Zhang. «Instead, it’s the alt-EJ pathway that drives circular production.»

“My lab is currently trying to test whether cyclic DNA can be a mediator for making new genomic inserts,” says Zhang. «We are also testing whether our immune system can sense circular DNA to trigger an immune response.»

“In the field of retroviruses and in the field of retrotransposons, people think that circular DNA is just a small event, but our study is taking circular DNA to the center stage,” said Zhang. «People should pay more attention to circular DNA.»

Authority to solve: Yang F, Su W, Chung OW, et al. Retrotransposons hijack alt-EJ for DNA replication and eccDNA biogenesis. Nature. 2023. doi: 10.1038/s41586-023-06327-7

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