Various repair mechanisms help our cells to revert damage to their DNA. If they fail, mutations accumulate in the genome that can lead to devastating diseases. DNA repair defects underlie predisposition to certain cancers and promote the transformation process in other spontaneous cancers.
DNA repair requires many factors, but so far there have not been comprehensive analyses of the intricate pathways involved. Using novel and highly sensitive proteomic technologies, scientists of the Max Planck Institute (MPI) of Biochemistry now report in the journal Science the first global analysis of the protein recruitment dynamics underlying a critical DNA repair pathway.
Their results shed light on the repair mechanism and identified new proteins and drug targets that could be important in maintaining genomic stability and preventing cancer.
During each cell division, more than 3.3 billion base pairs of genomic DNA have to be duplicated and segregated accurately to daughter cells. But what happens when the DNA template is damaged in such a way that the replication machinery gets stuck?
To answer this question, scientists in the team of Matthias Mann at the MPI of Biochemistry in Martinsried near Munich, with colleagues in Copenhagen and at Harvard, have analyzed how the protein composition of the DNA replication machinery changes upon encountering damaged DNA.
To monitor such changes, they isolated DNA at several time points during the replication and repair process, and quantified the bound proteins using mass spectrometry based proteomics. In contrast to the conventional approach of quantifying a few selected proteins, proteomic analysis allows the simultaneous quantification of thousands of proteins from a biological sample.
Using this unbiased approach, they found that as the replication machinery collides with lesions in the DNA more than 90 proteins are recruited to help repair the damaged DNA. These include many known DNA repair factors, as well as new proteins of previously unknown function. Together with the team of Professor Mailand at the Center for Protein Research in Copenhagen, Denmark, they are now analyzing whether and how these proteins promote the repair process.
“Many of these recruited proteins are essential for the faithful propagation of genomic information to daughter cells,” explains Markus Räschle, first author of the study. “Because defects in DNA repair pathways are commonly observed in genetically inherited cancer syndromes, such as familially inherited breast cancer, it is possible that mutations in the new factors may contribute to genetic predisposition to cancers.”
DNA modifying agents are among the most frequently used class of chemotherapeutics. They work particularly well if the cancer cells they attack already have defects in the corresponding DNA repair pathways, as it frequently occurs in breast cancer and other tumors.
Adaptation of proteomics for clinical diagnostics may open completely new possibilities. “Acquiring proteomic profiles directly from the tumor tissue may help oncologists to rapidly find the optimal class and dose of drugs,” says Matthias Mann, director at the Max Planck Institute of Biochemistry. “Our hope is that this approach may lead to more effective therapies with fewer side effects.”
M. Räschle, G. Smeenk, R.K. Hansen, T. Temu, Y. Oka, M.Y. Hein, N. Nagaraj, D.T. Long, J.C. Walter, K. Hofmann, Z. Storchova, J. Cox, S. Bekker-Jensen, N. Mailand, M. Mann: Proteomics reveals dynamic assembly of repair complexes during bypass of DNA crosslinks. Science, May 1, 2015
http://www.biochem.mpg.de/5003150/20150504_mann_dnareparatur - detailed press release
http://www.biochem.mpg.de/news/ueber_das_institut/forschungsbereiche/zellbiologi... - more texts about Matthias Mann's research
http://www.biochem.mpg.de/mann - website of the research department "Proteomics and Signal Transduction" (Matthias Mann)
Anja Konschak | Max-Planck-Institut für Biochemie
Hidden dynamics detected in neuronal networks
23.07.2019 | Forschungszentrum Juelich
Towards a light driven molecular assembler
23.07.2019 | Christian-Albrechts-Universität zu Kiel
Augsburg chemists and physicists report how they have succeeded in the extremely difficult separation of hydrogen and deuterium in a gas mixture.
Thanks to the Surface Acoustic Wave (SAW) technology developed here and already widely used, the University of Augsburg is internationally recognized as the...
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...
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...
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...
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...
24.06.2019 | Event News
29.04.2019 | Event News
17.04.2019 | Event News
23.07.2019 | Life Sciences
23.07.2019 | Life Sciences
23.07.2019 | Physics and Astronomy