Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Supercoiled DNA is far more dynamic than the 'Watson-Crick' double helix

13.10.2015

Researchers have imaged in unprecedented detail the three-dimensional structure of supercoiled DNA, revealing that its shape is much more dynamic than the well-known double helix.

Various DNA shapes, including figure-8s, were imaged using a powerful microscopy technique by researchers at the Baylor College of Medicine in the US, and then examined using supercomputer simulations run at the University of Leeds.


The image shows the structure of the DNA calculated with the supercomputer simulations (in colour) superimposed upon the cryo-electron tomography data (in white or yellow). (There is no superimposition onto cryo-electron tomography data for the purple figure-8 shape.) You can see that the familiar double helix has been either simply bent into a circle or twisted into a figure-8.

Credit: Thana Sutthibutpong

As reported online today in the journal Nature Communications, the simulations also show the dynamic nature of DNA, which constantly wiggles and morphs into different shapes - a far cry from the commonly held idea of a rigid and static double helix structure.

Improving our understanding of what DNA looks like when it is in the cell will help us to design better medicines, such as new antibiotics or more effective cancer chemotherapies.

Dr Sarah Harris from the School of Physics and Astronomy at the University of Leeds, who led the computer simulation research side of the study, said: "This is because the action of drug molecules relies on them recognising a specific molecular shape - much like a key fits a particular lock."

The double helix shape has a firm place in the public's collective consciousness. It is referenced in popular culture and often features in art and design. But the shape of DNA isn't always that simple.

Dr Harris said: "When Watson and Crick described the DNA double helix, they were looking at a tiny part of a real genome, only about one turn of the double helix. This is about 12 DNA 'base pairs', which are the building blocks of DNA that form the rungs of the helical ladder.

"Our study looks at DNA on a somewhat grander scale - several hundreds of base pairs - and even this relatively modest increase in size reveals a whole new richness in the behavior of the DNA molecule."

There are actually about 3 billion base pairs that make up the complete set of DNA instructions in humans. This is about a metre of DNA. This enormous string of molecular information has to be precisely organised by coiling it up tightly so that it can be squeezed into the nucleus of cells.

To study the structure of DNA when it is crammed into cells, the researchers needed to replicate this coiling of DNA.

Dr Lynn Zechiedrich, the corresponding author for the study from the Baylor College of Medicine, said: "You can't coil linear DNA and study it, so we had to make circles so the ends would trap the different degrees of winding."

To investigate how the winding changed what the circles looked like, the researchers wound and then unwound the tiny DNA circles - 10 million times shorter in length than the DNA contained within our cells - a single turn at a time.

The researchers devised a test to make sure that the tiny twisted up DNA circles that they made in the laboratory acted in the same way as the full-length DNA strands within our cells, when it is referred to as 'biologically active'.

They used an enzyme called 'human topoisomerase II alpha' that manipulates the twist of DNA. The test showed that the enzyme relieved the winding stress from all of the supercoiled circles, even the most coiled ones, which is its normal job in the human body. This result means that the DNA in the circles must look and act like the much longer DNA that the enzyme encounters in human cells.

Dr Rossitza Irobalieva, the co-lead author on the publication, who conducted the work while she was at Baylor, used 'cryo-electron tomography' - a powerful microscopy technique that involves freezing biologically active material - to provide the first three-dimensional images of individual circular DNA molecules. She saw that coiling the tiny DNA circles caused them to form a zoo of beautiful and unexpected shapes.

"Some of the circles had sharp bends, some were figure-8s, and others looked like handcuffs or racquets or even sewing needles. Some looked like rods because they were so coiled," said Dr Irobalieva.

The static images produced by the cryo-electron tomography were then compared to and matched with shapes generated in supercomputer simulations that were run at the University of Leeds. These simulated images provided a higher-resolution view of the DNA and show how its dynamic motion makes its shape constantly change to form a myriad of structures.

The cryo-electron tomography of the tiny DNA circles also revealed another surprise finding.

Base pairs in DNA are like a genetic alphabet, in which the letters on one side of the DNA double helix only pair with a particular letter on the other side. While the researchers expected to see the opening of base pairs - that is, the separation of the paired letters in the genetic alphabet - when the DNA was under-wound, they were surprised to see this opening for the over-wound DNA. This is because over-winding is supposed to make the DNA double helix stronger.

The researchers hypothesise that this disruption of base pairs may cause flexible hinges, allowing the DNA to bend sharply, perhaps helping to explain how a meter of DNA can be jammed into a single human cell.

Dr Harris concludes: "We are sure that supercomputers will play an increasingly important role in drug design. We are trying to do a puzzle with millions of pieces, and they all keep changing shape."

###

Further information

The research paper, 'The Structural Diversity of Supercoiled DNA', was published online today in Nature Communications.

Dr Sarah Harris received funding from the Biotechnology and Biological Sciences Research Council (BBSRC).

Dr Harris is available for interview. Please contact the University of Leeds press office on 0113 343 4031 or email pressoffice@leeds.ac.uk.

A team of researchers from a number of fields came together to address this fundamental problem. Their YouTube video explains the new results: https://www.youtube.com/watch?v=gwy2lD1reos

Images

Caption: The images show the structure of the DNA calculated with the supercomputer simulations (in colour) superimposed upon the cryo-electron tomography data (in white or yellow). (There is no superimposition onto cryo-electron tomography data for the purple figure-8 shape.) You can see that the familiar double helix has been either simply bent into a circle or twisted into a figure-8.

Download: https://goo.gl/OZWCxa

Credit: Thana Sutthibutpong

Movies

Caption: Supercomputer simulations show how the dynamic motion of the supercoiled DNA causes its shape to change constantly to form a myriad of structures.

Download: https://goo.gl/OvikoV

Credit: Thana Sutthibutpong

Sarah Reed | EurekAlert!

More articles from Life Sciences:

nachricht New technique for in-cell distance determination
19.03.2019 | Universität Konstanz

nachricht Dalian Coherent Light Source reveals hydroxyl super rotors from water photochemistry
19.03.2019 | Chinese Academy of Sciences Headquarters

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Stellar cartography

The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.

A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...

Im Focus: Heading towards a tsunami of light

Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.

"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...

Im Focus: Revealing the secret of the vacuum for the first time

New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum

For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...

Im Focus: Sussex scientists one step closer to a clock that could replace GPS and Galileo

Physicists in the EPic Lab at University of Sussex make crucial development in global race to develop a portable atomic clock

Scientists in the Emergent Photonics Lab (EPic Lab) at the University of Sussex have made a breakthrough to a crucial element of an atomic clock - devices...

Im Focus: Sensing shakes

A new way to sense earthquakes could help improve early warning systems

Every year earthquakes worldwide claim hundreds or even thousands of lives. Forewarning allows people to head for safety and a matter of seconds could spell...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

International Modelica Conference with 330 visitors from 21 countries at OTH Regensburg

11.03.2019 | Event News

Selection Completed: 580 Young Scientists from 88 Countries at the Lindau Nobel Laureate Meeting

01.03.2019 | Event News

LightMAT 2019 – 3rd International Conference on Light Materials – Science and Technology

28.02.2019 | Event News

 
Latest News

Levitating objects with light

19.03.2019 | Physics and Astronomy

New technique for in-cell distance determination

19.03.2019 | Life Sciences

Stellar cartography

19.03.2019 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>