Loebrich

Radiation Biology and DNA Repair

Prof. Dr. Markus Löbrich

Research

High-resolution microscopic image of an X-irradiated human cell which progressed into mitosis despite the presence of unrepaired DNA double-strand breaks (red: DNA; green: double-strand breaks). An Anaphase bridge and micronuclei detached from the bulk of the genome display unrepaired double-strand breaks.
High-resolution microscopic image of an X-irradiated human cell which progressed into mitosis despite the presence of unrepaired DNA double-strand breaks (red: DNA; green: double-strand breaks). An Anaphase bridge and micronuclei detached from the bulk of the genome display unrepaired double-strand breaks.

Understanding DNA damage response pathways is central not only for improving the efficacy of cancer radiotherapy but also for the protection of human beings from the carcinogenic effects of radiation encountered in the clinic and during daily life. Cells cope with radiation-induced DNA damage by initiating DNA repair pathways, cell cycle control mechanisms and, in case of excessive DNA damage, by the activation of apoptosis. DNA double-strand breaks (DSBs) represent important DNA lesions since they can lead to chromosomal rearrangements, which represent initiating events for the process of carcinogenesis. The two main pathways for repairing DSBs are non-homologous end-joining (NHEJ) and homologous recombination (HR). The factors and processes determining the choice between these pathways as well as the distinct fidelities of NHEJ and HR are important scientific areas under investigation.

The repair of DSBs after high-LET exposure

The aim of this project is to investigate the repair of DSBs induced by high-LET radiation in human cells. The experiments are performed at the GSI facilities in Darmstadt. It has been known for several years that high-LET-induced DSBs are generally more slowly repaired than breaks induced by X- or gamma-rays. Moreover, the level of residual DSBs after prolonged repair incubation appears to correlate with the cell killing capacity of a given radiation quality over a substantial LET range. It is, therefore, important to understand the basis of the compromised DSB repair kinetics of high-LET radiations.

Mechanisms involved in the response to DSBs

We were recently able to quantify the contribution of homologous recombination and non-homologous end joining for the repair of DSBs in defined cell cycle phases, and thereby provided a quantitative evaluation of the two major repair pathways for the repair of individual breaks that are produced in mammalian cells by DNA-damaging agents. We have also recently shown that cells from individuals with the neuro-degenerative and cancer-prone disease ataxia telangiectasia (AT) have a DSB rejoining defect after low doses used to monitor survival, and we have provided evidence that this DSB repair defect underlies the radiosensitivity of AT cells and cells from other patients with chromosomal instability syndromes. The current focus of this research direction lies in the molecular characterisation of the DSB repair defect in AT cells.

Clinical applications of the knowledge gained from DSB response studies

While DSB repair studies have hitherto been restricted to human cells in culture, immuno fluorescence microscopy offers the intriguing possibility to follow the repair process in humans. We have extended the methodological approach from cell culture systems to peripheral blood lymphocytes and were able to detect DSBs in humans that were exposed to diagnostic and therapeutic X-ray doses. This approach has allowed us to assess the extent of DNA damage after various time points following radiation exposure of individuals and, therefore, to quantify DSB repair processes in vivo.

Collaborative research projects:

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