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
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy