Project

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Binding of metal ions and organometallic compounds to oligonucleotides explored by mass spectrometry

Applicant Schürch Stefan
Number 121843
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie, Biochemie und Pharmazie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.03.2009 - 29.02.2012
Approved amount 167'396.00
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Keywords (10)

oligonucleotides; nucleic acids; tandem mass spectrometry; electrospray ionization; metal ions; anti-cancer drugs; oligonucleotide analysis; tandem mass spectrometry; dissociation mechanisms; cisplatin

Lay Summary (English)

Lead
Lay summary

Oligonucleotides play a central role in cellular processes, as they are the key elements responsible for storage and replication of genetic information and its conversion into proteins. Moreover, they exhibit manifold catalytic activities. Thus, it is not surprising that they have gained increased interest as targets for therapeutic approaches to fight diseases. Furthermore, oligonucleotide analogues have found application as drugs for human cancer therapy and much effort is put into the synthesis and evaluation of novel nucleic acid-based drug candidates. The exploration of cellular mechanisms as well as the development and evaluation of anti-cancer drugs require highly sensitive and accurate analytical tools. Electrospray tandem mass spectrometry is one of the preferred techniques for these tasks, as it is capable of handling the small amounts of material, while simultaneously providing detailed structural information.Results of research will be a significant addition to our understanding of the binding of metal ions and important anti-cancer drugs to oligonucleotides and provide fundamental information for future characterization of in-vitro and isolated in-vivo constructs. We can foresee significant impact of this research on medicinal and biological research regarding cancer treatment and apoptosis in general.


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Tandem Mass Spectrometry of Modified and Platinated Oligoribonucleotides
Nyakas Adrien, Stucki Silvan Remo, Schürch Stefan (2011), Tandem Mass Spectrometry of Modified and Platinated Oligoribonucleotides, in J. Am. Soc. Mass Spectrom., 22(5), 875-887.
Tandem mass spectrometry of platinated quadruplex DNA
Stucki Silvan Remo, Nyakas Adrien, Schürch Stefan (2011), Tandem mass spectrometry of platinated quadruplex DNA, in J. Mass Spectrom., 46(12), 1288-1297.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the Swiss Chemical Society Talk given at a conference Tandem Mass Spectrometry of Platinated DNA Quadruplexes 09.09.2011 Lausanne, Switzerland Schürch Stefan; Stucki Silvan;
59th ASMS Conference on Mass Spectrometry and Allied Topics Poster Tandem Mass Spectrometry of unplatinated and platinated DNA Quadruplexes 05.06.2011 Denver, CO, United States of America Stucki Silvan; Schürch Stefan;
Anakon Poster Insights into the Fragmentation of unplatinated and platinated DNA Quadruplexes 22.03.2011 Zürich, Switzerland Schürch Stefan; Stucki Silvan;
Annual Meeting of the Swiss Chemical Society Poster Investigation of DNA Quadruplex Structures by Electrospray Mass Spectromety 16.09.2010 Zürich, Switzerland Schürch Stefan; Stucki Silvan;


Awards

Title Year
SCNAT Travel Award 2011

Associated projects

Number Title Start Funding scheme
111877 Sequencing and detection of metal ion binding to oligo(ribo)nucleotides by tandem mass spectrometry 01.04.2006 Project funding (Div. I-III)
140628 Probing the interactions of organometallic compounds with nucleic acids by tandem mass spectrometry 01.04.2012 Project funding (Div. I-III)

Abstract

This research proposal is focused on the investigation of the complexes of oligonucleotides with metal ions and organometallic compounds by electrospray tandem mass spectrometry. Other analytical techniques, such as NMR and MALDI-TOF-MS will be used to provide complementary data on the solution- and gas-phase-structure of complexes. Support is requested for one graduate student position for a period of three years. Oligonucleotides play a central role in cellular processes, as they are the key elements responsible for storage and replication of genetic information and its conversion into protein. Moreover, they exhibit manifold catalytic activities. Thus, it is not surprising that they have gained increased interest as targets for therapeutic approaches to fight diseases. Furthermore, oligonucleotide analogues have found application as drugs for human cancer therapy and much effort is put into the synthesis and evaluation of novel nucleic acid-based drug candidates. The exploration of cellular mechanisms as well as the development and evaluation of anti-cancer drugs require highly sensitive and accurate analytical tools. Electrospray tandem mass spectrometry is one of the preferred techniques for these tasks, as it is capable of handling the small amounts of material, while simultaneously providing detailed structural information.Project A: Elucidation of the binding site, binding pattern, and binding stoichiometry of metal ions to single-stranded oligonucleotides:As a first sub-project we propose the investigation of metal ion binding to single- and double-stranded oligonucleotides (DNA and RNA) with the goal to elucidate the binding sites, binding motifs, and binding stoichiometry of metal ions. In addition to ESI-MS/MS analysis, work will include complementary methods, such as NMR and MALDI-TOF-MS, which will provide information about conservation of the solution-phase structure upon transfer into the gas-phase. NMR data on short oligonucleotides will be obtained in collaboration with the group of Prof. P. Bigler at our Department. Mass spectrometric experiments will also include longer oligonucleotide sequences, e.g. telomeric DNA. Metal ion coordination to oligonucleotides is not only required for charge neutralization, metal ions are also essential for proper structure formation and biological functioning of nucleic acids. Thus, there is a strong demand for characterization of metal-ion oligonucleotide complexes in order to elucidate structural properties of oligonucleotides in natural systems and to identify the pathways of cellular processes. ESI-MS/MS bears a great potential for this task and could turn into a valuable alternative to X-ray diffraction and NMR analysis.Project B: Tandem mass spectrometric investigation of the complexes formed between single- and double-stranded oligonucleotides and organometallic compounds:In a second sub-project we plan to investigate the complexes formed between oligonucleotides and organometallic mono- and dinuclear reagents. Elucidation of the gas-phase dissociation mechanisms of platinated oligonucleotides will provide the foundation for unambiguous determination of the binding motifs and binding sites of these important anticancer drugs. Once the fundamental mechanistic aspects will be solved, investigation of hairpin DNA, cross-linked double-stranded DNA, and G-quadruplex structures is planned. Tandem mass spectrometry can provide detailed information about various types of platinated oligonucleotides with respect to higher order structural aspects and cross-linking. Results of planned research will be a significant addition to our understanding of the binding of important anti-cancer drugs to oligonucleotides and provide fundamental information for future characterization of in-vitro and isolated in-vivo constructs. We can foresee significant impact of this research on medicinal and biological research regarding cancer treatment and apoptosis in general.
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