Long-range four-stranded DNA structures found to play a role in rare
aging disease

Date:
December 6, 2021
Source:
Imperial College London
Summary:
A special form of four-stranded DNA, recently seen in human cells,
has been found to interact with a gene that causes Cockayne Syndrome
when faulty.



FULL STORY ==========================================================================
A special form of four-stranded DNA, recently seen in human cells,
has been found to interact with a gene that causes Cockayne Syndrome
when faulty.


==========================================================================
As well as the classic double-helix, researchers have recently discovered
a whole host of other DNA strand configurations, including quadruple-helix
DNA, which forms knot-like structures called G-quadruplexes.

While many of these new DNA configurations have only been observed in
cells in dishes, G-quadruplexes have recently been observed in living
human cells.

However, their possible functions in cells have not been discovered.

Now, researchers from the Molecular Science Research Hub at Imperial
College London have observed a protein called Cockayne Syndrome B (CSB) preferentially interacting with one specific type of G-quadruplex. These special G- quadruplexes arise when distant parts of DNA interact,
something that researchers thought was impossible to form within cells.

Normally functioning CSB proteins do not cause any ill effects, but
mutations of the gene that produce CSB protein can cause the fatal
premature ageing disorder Cockayne Syndrome, which kills many sufferers
before adulthood.

The team found that CSB proteins with mutations that cause
Cockayne Syndrome are no longer able to interact with the long-range G-quadruplexes. While we don't yet know why this might be, the team's
results, published today in theJournal of the American Chemical Society, suggest that these long-range DNA G-quadruplexes are specifically linked
with the functional role of CSB.



==========================================================================
Lead researcher Dr Marco Di Antonio, from the Department of Chemistry at Imperial, said: "Our genomic DNA is more than two metres long, but is compressed into a space only a few microns in diameter. It shouldn't
therefore be a surprise that there are ways the long-range looped
structures are leveraged to compress DNA in more complex interactions
than we imagined.

"There is still so much we don't know about DNA, but our results show that
how and where G-quadruplex structures form affects their function, making
them more important biologically than previously thought." DNA strands
are incredibly long and are wound in tight structures to fit inside
our cells. Previously, researchers had assumed that G-quadruplexes form
only from regions of DNA that sit next to each other. However, the team discovered G-quadruplexes that are formed from parts of the DNA strand
that are spatially distant one from the other.

It's these G-quadruplexes that specifically interact with the CSB
protein. The team shows that CSB could potentially use the G-quadruplexes
to link together distant portions of the DNA.

Exactly what the interaction results in is yet to be determined,
but previous independent research found that cells without CSB have
difficulty processing the DNA around sequences with the potential to
form G-quadruplexes.

The Imperial team have now found that the mutated form of CSB that causes Cockayne Syndrome is specifically attracted to G-quadruplexes that link
distant DNA portions. This could mean further study of the mutated CSB
gene might reveal the specific biological function of these long-range
DNA structures.

Next, the researchers want to image the G-quadruplexes and the functional
CSB gene bound together to determine exactly what the relationship does: whether the CSB helps the G-quadruplex hold the two distant regions
of the DNA together, or whether CSB actually initiates the break-up of G-quadruplexes once they have completed their function, or a combination
of both.

First author of the study Denise Liano, from the Department of
Chemistry at Imperial, said: "There is currently no cure for
Cockayne Syndrome. But with further study into how G-quadruplexes
and the gene behind Cockayne Syndrome interact we can learn
details that will hopefully allow us to discover therapeutic
tools, such as designer molecules that can regulate the interaction
and fight back against the premature ageing caused by the disease." ========================================================================== Story Source: Materials provided by Imperial_College_London. Original
written by Hayley Dunning. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Denise Liano, Souroprobho Chowdhury, Marco Di Antonio. Cockayne
Syndrome
B Protein Selectively Resolves and Interact with Intermolecular DNA
G- Quadruplex Structures. Journal of the American Chemical Society,
2021; DOI: 10.1021/jacs.1c10745 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211206113054.htm

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