Forschungsprojekte

Accumulation of DNA damage in complex normal tissues after protracted low-dose radiation

The biological effects of low doses of ionizing radiation on the physiological function of normal tissues in living organisms are unclear. Ionizing radiation induces a variety of lesions of which DNA double-strand breaks (DSBs) are the biologically most significant, because unrepaired or misrepaired DSBs can lead to cell death and genomic instability. Using the laboratory mouse as an in-vivo system we established innovative and ultrasensitive methods to analyze the DNA damage response mechanisms in tissue-specific stem cells and differentiated cells of normal tissues chronically exposed to low radiation doses (10 mGy/ 100 mGy low-LET).

By immunofluorescence microscopy DNA damage foci (γH2AX, 53BP1) are enumerated to monitor radiation-induced DSBs and to quantitatively study their accumulation in stem and differentiated cells within their physiological tissue context. To characterize these radiation-induced DNA lesions at the single-molecule level, we established a transmission electron microscopy (TEM) approach to localize gold-labeled repair components (γH2AX, 53BP1, MDC1, Ku70-Ku80, DNA-PKcs, pATM) within the chromatin ultra-structure. Using this innovative, technically delicate combination of light microscopy and electron microscopy, we aim to delineate the precise molecular mechanisms involved in the DNA damage response of tissue-specific stem and differentiated cells after protracted low-dose radiation. A more thorough understanding of the impact of low-dose radiation on complex living organisms will help to establish quantitative risk estimates for humans.

Research funding:

Publications:

Fractionated low-dose radiation induces long-lasting inflammatory responses in the hippocampus. Schmal Z, Hammer B, Müller A, Rübe CE. Int J Radiat Oncol Biol Phys. 2021 Dec; doi: 10.1016/j.ijrobp.2021.07.007 PMID: 34280471 
 

DNA damage accumulation during fractionated low-dose radiation compromises hippocampal neurogenesis. Schmal Z, Isermann A, Hladik D, von Toerne C, Tapio S, Rübe CE. Radiother Oncol. 2019 Aug;137:45-54. PMID: 31063923 
 

Hair Follicle Stem Cell Faith Is Dependent on Chromatin Remodeling Capacity Following Low-Dose Radiation. Schuler N, Timm S, Rübe CE. Stem Cells. 2018 Apr;36(4):574-588. PMID: 29282803 
 

Ultrastructural Insights into the Biological Significance of Persisting DNA Damage Foci after Low Doses of Ionizing Radiation. Lorat Y, Schanz S, Rübe CE. Clin Cancer Res. 2016 Nov 1;22(21):5300-5311. Clin Cancer Res. 2016. PMID: 27199493 
 

Persistent DNA Damage in Spermatogonial Stem Cells After Fractionated Low-Dose Irradiation of Testicular Tissue. Grewenig A, Schuler N, Rübe CE. Int J Radiat Oncol Biol Phys. 2015 Aug 1;92(5):1123-1131. PMID: 26059351 
 

Even low doses of radiation lead to DNA damage accumulation in lung tissue according to the genetically-defined DNA repair capacity. Flockerzi E, Schanz S, Rübe CE. Radiother Oncol. 2014 May;111(2):212-8. PMID: 24746565 
 

Accumulation of DNA damage in complex normal tissues after protracted low-dose radiation. Schanz S, Schuler N, Lorat Y, Fan L, Kaestner L, Wennemuth G, Rübe C, Rübe CE. DNA Repair (Amst). 2012 Oct 1;11(10):823-32. PMID: 22947398 
 

Inducible response required for repair of low-dose radiation damage in human fibroblasts. Grudzenski S, Raths A, Conrad S, Rübe CE, Löbrich M. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14205-10. PMID: 20660770