Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A new mechanism for accessing damaged DNA

03.06.2019

UV light damages the DNA of skin cells, which can lead to skin cancer. But this process is counteracted by the DNA repair machinery, acting as a molecular sunscreen. It has been unclear, however, how repair proteins work on DNA tightly packed in chromatin, where access to DNA damage is restricted by protein packaging. Using cryo electron microscopy, researchers from the Thomä group at the Friedrich Miescher Institute for Biomedical Research (FMI) have identified a new mechanism whereby repair proteins detect and bind to damaged DNA that is densely packed in nucleosomes.

Ultraviolet (UV) light damages DNA, producing small lesions. These UV lesions are first detected by a protein complex known as UV-DDB and - once the lesions have been identified - the rest of the DNA repair machinery swings into action.


Cryo-EM map of a molecule of UV-DDB (right) binding to DNA wrapped around a histone (left).

Credit: FMI

The question is, how can UV-DDB bind to lesions when the DNA is coiled around the histone protein core of the so-called nucleosome (the basic unit of chromatin - the DNA packaging of eukaryotic chromosomes)?

To gain access, UV-DDB was previously thought to require the assistance of additional proteins that shift the nucleosome. Researchers from the group led by Nicolas Thomä have now found that additional proteins are not necessarily needed to detect UV-induced lesions; instead, the UV-DDB complex takes advantage of the intrinsic dynamics of nucleosomal DNA. The DNA repair factor appears to catch the UV lesions when they are temporarily accessible.

In their study published in Nature, the scientists determined various three dimensional (3D) structures of UV-DDB bound to lesions at different locations around the nucleosome, using cryo-electron microscopy - a technique that allows the 3D structure of biomolecules to be visualized with atomic detail.

The researchers concluded that damage detection strategies depend on where the DNA lesion is located. In the case of "accessible" lesions, which can be directly contacted, UV-DDB binds to the lesion tightly. The recognition of "occluded" lesions (facing the histone protein core of the nucleosome) requires additional steps: UV-DDB binds the UV lesions when they are exposed temporarily through the natural dynamics of the nucleosome.

One of the lead authors, Syota Matsumoto, explains: "To visualize what happens at the molecular level, imagine a piece of string wrapped around a spool, which becomes accessible when it is pulled forwards or backwards a little bit."

The researchers called the mechanism of DNA damage read-out "slide-assisted site-exposure". This new mechanism operates independently of chromatin remodelers and does not require chemical energy to slide or dislodge nucleosomes.

Thomä comments: "In the past, nucleosomes were thought to be a major obstacle for DNA-binding proteins. In our study, we show that they are not, and that the system is tailored to bind UV lesions wherever they are.

What makes this study really powerful is the fact that the mechanism we identified could very well be used by many other types of DNA-binding proteins. Accessing nucleosomal DNA is not only fundamental for DNA repair, but is relevant for all proteins that bind to chromatin. With our study, we define a previously unknown strategy for protein access to chromatinized DNA templates."

###

Original publication

Syota Matsumoto*, Simone Cavadini*, Richard D. Bunker*, Ralph S. Grand, Alessandro Potenza, Julius Rabl, Junpei Yamamoto, Andreas D. Schenk, Dirk Schübeler, Shigenori Iwai, Kaoru Sugasawa, Hitoshi Kurumizaka, Nicolas H. Thomä (2019) DNA damage detection in nucleosomes involves DNA register shifting. Nature, published online on May 29, 2019
*these authors contributed equally.

Contact

Dr Nicolas Thomä, nicolas.thoma@fmi.ch, Tel: + 41 (0)61 697 86 30

Nicolas Thomä is a Senior Group Leader at the FMI. With his research group he is interested in the machinery that controls the integrity of the DNA. The researchers combine X-ray crystallography and cryo-electron microscopy with biochemical and biophysical studies to better understand large protein complexes involved in crucial cellular functions such as DNA repair, telomere maintenance and epigenetics in health and disease.

» More about the Thomä group

About the FMI

The Friedrich Miescher Institute for Biomedical Research (FMI), based in Basel, Switzerland, is a world-class biomedical research institute dedicated to understanding the molecular mechanisms of health and disease. Its main areas of expertise are neurobiology, quantitative biology and epigenetics. With a staff of about 350, the FMI offers an exceptional training environment for PhD students and postdoctoral fellows from around the world. The FMI is affiliated with the University of Basel and the Novartis Institutes for BioMedical Research, and is currently being co-led by Silvia Arber and Dirk Schübeler.

» More about the FMI

Media Contact

Isabelle Baumann
isabelle.baumann@fmi.ch
41-616-961-539

http://www.fmi.ch 

Isabelle Baumann | EurekAlert!
Further information:
https://www.fmi.ch/news/releases/articles/?news=409
http://dx.doi.org/10.1038/s41586-019-1259-3

More articles from Life Sciences:

nachricht If Machines Could Smell ...
19.07.2019 | Fraunhofer-Institut für Produktionstechnik und Automatisierung IPA

nachricht Algae-killing viruses spur nutrient recycling in oceans
18.07.2019 | Rutgers University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Better thermal conductivity by adjusting the arrangement of atoms

Adjusting the thermal conductivity of materials is one of the challenges nanoscience is currently facing. Together with colleagues from the Netherlands and Spain, researchers from the University of Basel have shown that the atomic vibrations that determine heat generation in nanowires can be controlled through the arrangement of atoms alone. The scientists will publish the results shortly in the journal Nano Letters.

In the electronics and computer industry, components are becoming ever smaller and more powerful. However, there are problems with the heat generation. It is...

Im Focus: First-ever visualizations of electrical gating effects on electronic structure

Scientists have visualised the electronic structure in a microelectronic device for the first time, opening up opportunities for finely-tuned high performance electronic devices.

Physicists from the University of Warwick and the University of Washington have developed a technique to measure the energy and momentum of electrons in...

Im Focus: Megakaryocytes act as „bouncers“ restraining cell migration in the bone marrow

Scientists at the University Würzburg and University Hospital of Würzburg found that megakaryocytes act as “bouncers” and thus modulate bone marrow niche properties and cell migration dynamics. The study was published in July in the Journal “Haematologica”.

Hematopoiesis is the process of forming blood cells, which occurs predominantly in the bone marrow. The bone marrow produces all types of blood cells: red...

Im Focus: Artificial neural network resolves puzzles from condensed matter physics: Which is the perfect quantum theory?

For some phenomena in quantum many-body physics several competing theories exist. But which of them describes a quantum phenomenon best? A team of researchers from the Technical University of Munich (TUM) and Harvard University in the United States has now successfully deployed artificial neural networks for image analysis of quantum systems.

Is that a dog or a cat? Such a classification is a prime example of machine learning: artificial neural networks can be trained to analyze images by looking...

Im Focus: Extremely hard yet metallically conductive: Bayreuth researchers develop novel material with high-tech prospects

An international research group led by scientists from the University of Bayreuth has produced a previously unknown material: Rhenium nitride pernitride. Thanks to combining properties that were previously considered incompatible, it looks set to become highly attractive for technological applications. Indeed, it is a super-hard metallic conductor that can withstand extremely high pressures like a diamond. A process now developed in Bayreuth opens up the possibility of producing rhenium nitride pernitride and other technologically interesting materials in sufficiently large quantity for their properties characterisation. The new findings are presented in "Nature Communications".

The possibility of finding a compound that was metallically conductive, super-hard, and ultra-incompressible was long considered unlikely in science. It was...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on UV LED Technologies & Applications – ICULTA 2020 | Call for Abstracts

24.06.2019 | Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

 
Latest News

Heat flow through single molecules detected

19.07.2019 | Physics and Astronomy

Heat transport through single molecules

19.07.2019 | Physics and Astronomy

Welcome Committee for Comets

19.07.2019 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>