MSGID: 1:317/3 64af7df4   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    DNA element with a murky past is borrowing cell's repair machinery   
    Circular DNA, thought to be an accidental byproduct, is borrowing the   
   cell's DNA repair mechanisms to copy itself    
      
     Date:   
         July 12, 2023   
     Source:   
         Duke University   
     Summary:   
         Like their viral cousins, retrotransposons have been found borrowing   
         the cell's own machinery to achieve their goals. They hijack a   
         little-known piece of the cell's DNA repair function to close   
         themselves into a ring- like shape and then create a matching   
         double strand. The finding upends 40 years of conventional wisdom   
         and may offer new insights into cancer, viral infections and immune   
         responses. It could also offer a new way to insert sequences into   
         the genome.   
      
      
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   Like its viral cousins, a somewhat parasitic DNA sequence called a   
   retrotransposon has been found borrowing the cell's own machinery to   
   achieve its goals.   
      
   In a new work appearing online Wednesday in the journal Nature,   
   a Duke University team has determined that retrotransposons hijack a   
   little-known piece of the cell's DNA repair function to close themselves   
   into a ring-like shape and then create a matching double strand.   
      
   The finding upends 40 years of conventional wisdom saying these rings   
   were just a useless by-product of bad gene copying. It may also offer   
   new insights into cancer, viral infections and immune responses.   
      
   Retrotransposons are segments of DNA around 7,000 letters long that   
   copy and paste themselves into different parts of the genomes of both   
   plants and animals. By doing this, they play a role in rewriting DNA and   
   regulating how the cell uses its genes. Retrotransposons are believed   
   to be behind a lot of the variation and innovation in genes that drives   
   evolution, and are inherited from both parents.   
      
   Many studies have suggested that these rings of DNA outside the   
   chromosomes are somehow involved in the development and progression of   
   cancer in part because they are known to harbor cancer-driving oncogenes   
   within their DNA sequences.   
      
   The retrovirus HIV, which causes AIDS, is also known to form circular DNA.   
      
   "I think these elements are the source of genome dynamics, for animal   
   evolution and even to affect our daily lives," said Zhao Zhang (ZZ), an   
   assistant professor of pharmacology and cancer biology and a Duke Science   
   & Technology scholar. "But we are still in the process of appreciating   
   their function."  Retrotransposons are quite common -- they make up   
   about 40% of the human genome, and more than 75% of the maize genome --   
   but how and where they copy themselves has always been a bit murky.   
      
   Zhang holds up a thick textbook on retroviruses that he consulted for this   
   study. The books say the ring-like sequences are "created by recombining   
   the two ends of linear DNA, and are just a dead end, a by-product of   
   failed replication," he said.   
      
   In earlier work with fruit fly eggs, Zhang's team had established that   
   inherited retrotransposons use the 'nurse cells' which support the egg   
   as factories to manufacture many copies of themselves that are then   
   distributed throughout the genome in the fly's developing egg. This   
   model system allowed the researchers to zoom in still further to learn   
   more about retrotransposons.   
      
   In the latest work, they found unexpectedly that most newly added   
   retrotransposons were in this circular form rather than being integrated   
   into the host's genome. Then they ran a series of experiments knocking   
   out the cell's DNA repair mechanisms one at a time to figure out how   
   and where the circles are being formed.   
      
   The answer: A little-studied DNA repair mechanism called alternative end-   
   joining DNA repair, or alt-EJ for short, which repairs doubles-stranded   
   breaks.   
      
   The retrotransposon sequences were using this part of the host's repair   
   machinery to sew the ends of their single-stranded DNA together and   
   then using its DNA synthase to create a matching double-strand. For good   
   measure, the researchers confirmed that this is also the process within   
   human cells.   
      
   So retrotransposons aren't a sloppy accident; they're actually hijacking   
   a little bit of the cell's machinery to manufacture more of themselves,   
   just like viruses do.   
      
   "Our discovery actually overturns the textbook model," Zhang said. "We   
   showed that the recombination event proposed by the textbook is not   
   important to forming rings," Zhang said. "Instead, it's the alt-EJ   
   pathway driving circle production."  "My lab currently is trying to   
   test whether circular DNA can be an intermediate to make new genome   
   insertions," Zhang said. "We're also testing whether circular DNA can   
   be sensed by our immune system to trigger an immune response."  "In the   
   retroviral field and retrotransposon field, people think circular DNA   
   is just a minor event, but our study is bringing circular DNA into   
   the center stage," Zhang said. "People should pay more attention to   
   circular DNA."  Funding for this study came from the National Cancer   
   Institute (P01CA247773), National Institutes of Health (DP5 OD021355,   
   R01 GM141018) and the Pew Biomedical Scholars Program.   
      
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   Journal Reference:   
      1. Fu Yang, Weijia Su, Oliver W. Chung, Lauren Tracy, Lu Wang, Dale A.   
      
         Ramsden, ZZ Zhao Zhang. Retrotransposons hijack alt-EJ for   
         DNA replication and eccDNA biogenesis. Nature, 2023; DOI:   
         10.1038/s41586-023- 06327-7   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230712124629.htm   
      
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