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 Antibiotics: New substances break bacterial resistance
12.11.2019 | Martin-Luther-Universität Halle-Wittenberg

nachricht How the Zika virus can spread
11.11.2019 | Goethe-Universität Frankfurt am Main

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A new quantum data classification protocol brings us nearer to a future 'quantum internet'

The algorithm represents a first step in the automated learning of quantum information networks

Quantum-based communication and computation technologies promise unprecedented applications, such as unconditionally secure communications, ultra-precise...

Im Focus: Distorted Atoms

In two experiments performed at the free-electron laser FLASH in Hamburg a cooperation led by physicists from the Heidelberg Max Planck Institute for Nuclear physics (MPIK) demonstrated strongly-driven nonlinear interaction of ultrashort extreme-ultraviolet (XUV) laser pulses with atoms and ions. The powerful excitation of an electron pair in helium was found to compete with the ultrafast decay, which temporarily may even lead to population inversion. Resonant transitions in doubly charged neon ions were shifted in energy, and observed by XUV-XUV pump-probe transient absorption spectroscopy.

An international team led by physicists from the MPIK reports on new results for efficient two-electron excitations in helium driven by strong and ultrashort...

Im Focus: A Memory Effect at Single-Atom Level

An international research group has observed new quantum properties on an artificial giant atom and has now published its results in the high-ranking journal Nature Physics. The quantum system under investigation apparently has a memory - a new finding that could be used to build a quantum computer.

The research group, consisting of German, Swedish and Indian scientists, has investigated an artificial quantum system and found new properties.

Im Focus: Shedding new light on the charging of lithium-ion batteries

Exposing cathodes to light decreases charge time by a factor of two in lithium-ion batteries.

Researchers at the U.S. Department of Energy's (DOE) Argonne National Laboratory have reported a new mechanism to speed up the charging of lithium-ion...

Im Focus: Visible light and nanoparticle catalysts produce desirable bioactive molecules

Simple photochemical method takes advantage of quantum mechanics

Northwestern University chemists have used visible light and extremely tiny nanoparticles to quickly and simply make molecules that are of the same class as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

High entropy alloys for hot turbines and tireless metal-forming presses

05.11.2019 | Event News

Smart lasers open up new applications and are the “tool of choice” in digitalization

30.10.2019 | Event News

International Symposium on Functional Materials for Electrolysis, Fuel Cells and Metal-Air Batteries

02.10.2019 | Event News

 
Latest News

How the Zika virus can spread

11.11.2019 | Life Sciences

Researchers find new potential approach to type 2 diabetes treatment

11.11.2019 | Health and Medicine

Medica 2019: Arteriosclerosis - new technologies help to find proper catheters and location of vasoconstriction

11.11.2019 | Trade Fair News

VideoLinks
Science & Research
Overview of more VideoLinks >>>