Principal Investigator

Prof. Dr. phil. nat. George Iliakis

Institute of Medical Radiation Biology
Essen University Hospital

Prof. Dr. George Iliakis

Summary

The majority of cells in the human body are differentiated and non-proliferating, whereas tumors comprise less differentiated cells that are frequently dividing. The proliferative status of a cell population is a major determinant of its distribution throughout cell cycle, of DNA double strand break (DSB) repair pathway choice and, thus, of its overall radiation response.

In addition to homologous recombination repair (HRR), which requires a sister chromatid and is therefore active only in S and G₂ phase of the cell cycle, cells of higher eukaryotes also utilize non-homologous end joining pathways for the processing of inflicted DSBs. Classical, DNA-PKcs-dependent non-homologous end joining (c-NHEJ) shows very small activity fluctuations throughout the cell cycle and in non-proliferating G₀ cells. An alternative pathway of end joining (alt-EJ) operates as backup to abrogated c-NHEJ and HRR and shows marked efficiency fluctuations with changing proliferation status. Notably, it becomes severely compromised when cells cease proliferating and enter G₀ phase. Previous results from our laboratory show that the deficiency of alt-EJ in non-proliferating G₀ cells is pronounced in all c-NHEJ mutants, with the notable exception of DNA-PKcs mutants, which show no reduction in alt-EJ activity as non-proliferating G₀ cells.

In this project we investigate the regulatory mechanisms by which alt-EJ is suppressed in non-proliferating cells and explore why this suppression requires DNA-PKcs. Particular emphasis is placed on the effects of proliferation-regulating growth-factor signaling, and its potential interactions with DNA-PKcs. The project is a component of our efforts to understand healthy and tumor tissue-response to radiation therapy, and to identify and characterize the molecular and mechanistic underpinnings of differential responses. Ultimate goal is to exploit such differential responses in the optimization of cancer therapy.

Selected Publications

Schipler A, Mladenova V, Soni A, Nikolov V, Saha J, Mladenov E, Iliakis G. Chromosome thripsis by DNA double strand break clusters causes enhanced cell lethality, chromosomal translocations and 53BP1-recruitment. Nucleic Acids Res 2016, 44: 7673-7690

van den Boom J, Wolf M, Weimann L, Schulze N, Li F, Kaschani F, Riemer A, Zierhut C, Kaiser M, Iliakis G, Funabiki H, Meyer H. VCP/p97 extracts sterically trapped Ku70/80 rings from DNA in double-strand break repair. Mol Cell 2016, 64: 189-198

Cheng Y, Li F, Mladenov E, Iliakis G. The yield of DNA double strand breaks determined after exclusion of those forming from heat-labile lesions predicts tumor cell radiosensitivity to killing. Radiother Oncol 2015, 116: 366-373

Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E, Helleday T, Haber JE, Iliakis G, Kallioniemi OP, Halazonetis TD Break-Induced Replication Repair of Damaged Forks Induced Genomic Duplications in Human Cells. Science 2014, 343: 88-91

Soni A, Siemann M, Grabos M, Murmann T, Pantelias GE, Iliakis G Requirement for Parp-1 and DNA ligases 1 or 3 but not of Xrcc1 in chromosomal translocation formation by backup end joining. Nucleic Acids Research 2014, 42: 6380-6392

Dueva R, Iliakis G. Alternative pathways of non-homologous end joining (NHEJ) in genomic instability and cancer. Transl Cancer Res 2013, 2: 163-177

Schipler A, Iliakis G DNA double-strand-break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice. Nucleic Acids Res 2013, 41: 7589-7605

Sing SK, Bednar T, Zhang L, Wu W, Mladenov E, Iliakis G Inhibition of B-NHEJ in Plateau-Phase Cells Is Not a Direct Consequence of Suppressed Growth Factor Signaling. Int J Radiat Oncol Biol Phys 2012, 84: e237-e243

Arakawa H, Bednar T, Wang M, Paul K, Mladenov E, Bencsik-Theilen AA, Iliakis G Functional redundancy between DNA ligases I and III in DNA replication in vertebrate cells. Nucleic Acids Res 2012, 40: 2599-2610