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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FULL STORY ==========================================================================
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.

* RELATED_TOPICS
o Health_&_Medicine
# Genes # Human_Biology # Diseases_and_Conditions #
Forensics
o Plants_&_Animals
# Biochemistry_Research # Developmental_Biology #
Biotechnology # Biology
* RELATED_TERMS
o DNA_repair o Natural_killer_cell o Immune_system o
Genetic_code o Protein o Gene_therapy o Computational_genomics
o DNA

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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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/07/230712124629.htm

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