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VIP: Research Team of TU Dort­mund Uni­ver­sity Publishes “Very Important Paper“

Very Precise Distance Measurements in DNA G-Qua­dru­plex Structures

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One woman and three men standing in a laboratory © Shari Meichsner​/​TU Dort­mund
JProf. Müge Kasan­mascheff, Prof. Guido Clever, Dr. Yury Kutin and Lukas Stratmann (from the left) were able to develop a method for the precise distance measurement in pairs of G qua­dru­plexes with or without bound drug-like mol­ecules.

DNA G-qua­dru­plexes play im­por­tant roles in biological processes and have been identified as promising drug targets, e.g. in anticancer re­search. In an inter­dis­ci­plin­ary collaboration between the laboratories of Prof. Guido Clever and Jun.-Prof. Müge Kasan­mascheff, both at TU Dort­mund Uni­ver­sity, a method for the precise distance measurement in pairs of G-qua­dru­plexes with or without bound drug-like mol­ecules was developed. The remarkable accuracy of this method allows elucidating the structure of such DNA adducts and provides evidence for intercalated compounds.

Human DNA usually adopts a helical, double stranded structure. However, also four-stranded variants (so-called G‑qua­dru­plexes) are known to form from guanine-rich sequences, resembling columnar stacks. In the past years, more and more evidence for biological functions and medicinal relevance of these DNA species was revealed. To understand the role of G‑qua­dru­plexes in the body, their architecture and structure must be elucidated. This is a challenging task, since these special DNA motifs show a high structural diversity. Once spatial structure and biological function are unraveled, small mol­ecules can be specifically designed to bind to these G‑qua­dru­plexes and manipulate their function. Since G‑qua­dru­plexes are thought to play crucial roles in different cancer types and also HIV infection and Malaria, such DNA-binding mol­ecules may show potential application as drugs.

In addition, G‑qua­dru­plexes are known to form higher-ordered structures. For example, they can assemble pairwise and form so-called dimers. Intercalation of small, usually flat mol­ecules into these dimers results in sandwich complexes. It has been difficult to reveal the formation of these nanometer-sized dimers and sandwich structures and even more so to measure their spatial dimension. In close cooperation, the re­search groups of Jun.-Prof. Müge Kasan­mascheff and Prof. Guido Clever at TU Dort­mund Uni­ver­sity have re­cent­ly been successful in developing a method that allows detecting such structures in solution with unprecedented accuracy.

Gif showing two DNA structures © Lukas Stratmann​/​TU Dort­mund
Intercalation of small, usually flat mol­ecules into dimers results in sandwich complexes.

A strategy in­clu­ding the precise incorporation of copper ions into chemically modified DNA G‑qua­dru­plexes enables distance measurements between unpaired electrons in both halves of the G-quadruplex dimers by a technique called EPR spectroscopy. Small mol­ecules, usually not soluble in water, were intercalated into the dimers in aqueous solution, resulting in a characteristically increased distance between the copper complexes. Due to the tight and rigid binding of the copper ions in the G‑qua­dru­plexes, distances were obtained with remarkable precision.

The proj­ect was realized within the RESOLV cluster of excellence funded by the German Research Foun­da­tion (DFG) and re­cent­ly published as an open access paper in the journal An­ge­wand­te Chemie. It was selected as a Very Important Paper. The presented method is of particular importance for structure elucidation of DNA G-quadruplex adducts and promises to facilitate the search for novel pharmacologically active mol­ecules.

Original publication:
“Precise Distance Measurements in DNA G‐Qua­dru­plex Dimers and Sandwich Complexes by Pulsed Dipolar EPR Spectroscopy”
L. M. Stratmann, Y. Kutin, M. Kasan­mascheff, G. H. Clever, Angew. Chem. Int. Ed. 2020, accepted, DOI: 10.1002/anie.202008618 (VIP Paper)
https://www.onlinelibrary.wiley.com/doi/10.1002/anie.202008618

Contact for further in­for­mation:

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The campus of TU Dort­mund Uni­ver­sity is located close to interstate junction Dort­mund West, where the Sauerlandlinie A 45 (Frankfurt-Dort­mund) crosses the Ruhrschnellweg B 1 / A 40. The best interstate exit to take from A 45 is “Dort­mund-Eichlinghofen” (closer to South Campus), and from B 1 / A 40 “Dort­mund-Dorstfeld” (closer to North Campus). Signs for the uni­ver­si­ty are located at both exits. Also, there is a new exit before you pass over the B 1-bridge leading into Dort­mund.

To get from North Campus to South Campus by car, there is the connection via Vo­gel­pothsweg/Baroper Straße. We recommend you leave your car on one of the parking lots at North Campus and use the H-Bahn (suspended monorail system), which conveniently connects the two campuses.

TU Dort­mund Uni­ver­sity has its own train station (“Dort­mund Uni­ver­si­tät”). From there, suburban trains (S-Bahn) leave for Dort­mund main station (“Dort­mund Hauptbahnhof”) and Düsseldorf main station via the “Düsseldorf Airport Train Station” (take S-Bahn number 1, which leaves every 20 or 30 minutes). The uni­ver­si­ty is easily reached from Bochum, Essen, Mülheim an der Ruhr and Duisburg.

You can also take the bus or subway train from Dort­mund city to the uni­ver­si­ty: From Dort­mund main station, you can take any train bound for the Station “Stadtgarten”, usually lines U41, U45, U 47 and U49. At “Stadtgarten” you switch trains and get on line U42 towards “Hombruch”. Look out for the Station “An der Palmweide”. From the bus stop just across the road, busses bound for TU Dort­mund Uni­ver­sity leave every ten minutes (445, 447 and 462). Another option is to take the subway routes U41, U45, U47 and U49 from Dort­mund main station to the stop “Dort­mund Kampstraße”. From there, take U43 or U44 to the stop “Dort­mund Wittener Straße”. Switch to bus line 447 and get off at “Dort­mund Uni­ver­si­tät S”.

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