Untersuchungen zum Mechanismus der Auswahl eines Reparaturweges bei der Verarbeitung von ionisierender Strahlung induzierten DNA Doppelstrangbrüchen
Zusammenfassung der Projektergebnisse
Breaks in the DNA that cut the molecule in pieces are called DNA double strand breaks (DSBs) and are very dangerous for the cell because they are very difficult to repair correctly. DSBs are induced by x-rays and charged particles present in the environment on earth and in space, but are also induced by radiations used to diagnose diseases and to treat cancer. Cells have four ways to repair DSBs, but only one of them does a perfect job. The one that is actually very often used by the cell is fast but makes mistakes. So, the question arises how the cell decides what repair way to use. Some researchers think that the decision is random and depends upon what repair protein happens to be close to the break at the moment it is generated. Since we found this model intellectually unsatisfying, we searched in this project for alternative explanations and developed ways to test its validity experimentally. The project focused on a protein named KU that is a key component of the fast but erroneous way of DSB repair, and MRE11, which in many ways initiates the pathway that does the perfect job. In a set of biochemical and genetic experiments we provide evidence for interaction between the two proteins that guides a transition of the DSB from erroneous to processing. While a lot more work will be needed to demonstrate the validity and generate more details of the model in cells, the results generated pave the way for such research in the future. We anticipate that such research will help to develop means to protect people from the adverse effects of radiation and to improve the radiotherapy of cancer therapy.
Projektbezogene Publikationen (Auswahl)
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DNA-PKcs and ATM epistatically suppress DNA end resection and hyperactivation of ATR-dependent G2-checkpoint in S-phase irradiated cells. Scientific Reports, 9(1).
Mladenov, Emil; Fan, Xiaoxiang; Paul-Konietzko, Katja; Soni, Aashish & Iliakis, George
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Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer. Cancers, 11(11), 1671.
Iliakis, George; Mladenov, Emil & Mladenova, Veronika
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Radiation-dose-dependent functional synergisms between ATM, ATR and DNA-PKcs in checkpoint control and resection in G2-phase. Scientific Reports, 9(1).
Mladenov, Emil; Fan, Xiaoxiang; Dueva, Rositsa; Soni, Aashish & Iliakis, George
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Strong suppression of gene conversion with increasing DNA double-strand break load delimited by 53BP1 and RAD52. Nucleic Acids Research, 48(4), 1905-1924.
Mladenov, Emil; Staudt, Christian; Soni, Aashish; Murmann-Konda, Tamara; Siemann-Loekes, Maria & Iliakis, George
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Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond. NAR Cancer, 2(3).
Dueva, Rositsa & Iliakis, George
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BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy. Cancers, 14(22), 5619.
Soni, Aashish; Lin, Xixi; Mladenov, Emil; Mladenova, Veronika; Stuschke, Martin & Iliakis, George
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Increased Gene Targeting in Hyper-Recombinogenic LymphoBlastoid Cell Lines Leaves Unchanged DSB Processing by Homologous Recombination. International Journal of Molecular Sciences, 23(16), 9180.
Mladenov, Emil; Paul-Konietzko, Katja; Mladenova, Veronika; Stuschke, Martin & Iliakis, George
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Increased Resection at DSBs in G2-Phase Is a Unique Phenotype Associated with DNA-PKcs Defects That Is Not Shared by Other Factors of c-NHEJ. Cells, 11(13), 2099.
Xiao, Huaping; Li, Fanghua; Mladenov, Emil; Soni, Aashish; Mladenova, Veronika; Pan, Bing; Dueva, Rositsa; Stuschke, Martin; Timmermann, Beate & Iliakis, George
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PTEN Loss Enhances Error-Prone DSB Processing and Tumor Cell Radiosensitivity by Suppressing RAD51 Expression and Homologous Recombination. International Journal of Molecular Sciences, 23(21), 12876.
Pei, Xile; Mladenov, Emil; Soni, Aashish; Li, Fanghua; Stuschke, Martin & Iliakis, George
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Low CDK Activity and Enhanced Degradation by APC/CCDH1 Abolishes CtIP Activity and Alt-EJ in Quiescent Cells. Cells, 12(11), 1530.
Li, Fanghua; Mladenov, Emil; Sun, Yanjie; Soni, Aashish; Stuschke, Martin; Timmermann, Beate & Iliakis, George
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New Facets of DNA Double Strand Break Repair: Radiation Dose as Key Determinant of HR versus c-NHEJ Engagement. International Journal of Molecular Sciences, 24(19), 14956.
Mladenov, Emil; Mladenova, Veronika; Stuschke, Martin & Iliakis, George
