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Factors modifying cellular response to ionizing radiation
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. (Andrzej Wojcik group)ORCID iD: 0000-0002-0984-6964
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Many physical factors influence the biological effect of exposure to ionizing radiation, including radiation quality, dose rate and temperature. This thesis focuses on how these factors influence the outcome of exposure and the mechanisms behind the cellular response. 

Mixed beam exposure, which is the combination of different ionizing radiations, occurs in many situations and the effects are important to understand for radiation protection and effect prediction. Recently, studies show that the effect of simultaneous irradiation with different qualities is greater than simple additivity of single radiation types, which is called a synergistic effect. But its mechanism is unclear. In Paper I, II and III, alpha particles and X-rays were used to study the effect of mixed beams. Paper I shows that mixed exposure induced a synergistic effect in generating double strand breaks (DSB), and these DSB were repaired by slow kinetics in U2OS cells. In Paper II, alkaline comet assay was applied to investigate the induction and repair of DNA lesions including DSB, single strand breaks and alkali labile sites in peripheral blood lymphocytes (PBL). We demonstrate that mixed beams interact in inducing DNA damage and influencing DNA damage response (DDR), which result in a delay of DNA repair. Both in Paper I and II, mixed beams showed a capability in inducing higher activity of DDR proteins than expected from additivity. Paper III investigates selected DDR-related gene expression levels after exposure to mixed beams in PBL from 4 donors. Synergy was present for all donors but the results suggested individual variability in the response to mixed beams, most likely due to life style changes.

Low temperature at exposure is radioprotective at the level of cytogenetic damage. In Paper IV, data indicate that this effect is through promotion of DNA repair, which leads to reduced transformation of DNA damage into chromosomal aberrations.  

Paper V aims to compare the biological effectiveness of gamma radiation delivered at a very high dose rate (VHDR) with that of a high dose rate (HDR) in order to optimize chronic exposure risk prediction based on the data of atomic bomb survivors. The results suggest that VHDR gamma radiation is more effective in inducing DNA damage than HDR.     

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Bioscience, The Winner-Gren Institute, Stockholm University , 2019. , p. 48
Keywords [en]
Radiation biology, DNA damage, gene expression, alpha particles, X-rays, mixed beams, gamma rays, hypothermia, dose rate.
National Category
Other Biological Topics
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-168023ISBN: 978-91-7797-725-4 (print)ISBN: 978-91-7797-726-1 (electronic)OAI: oai:DiVA.org:su-168023DiVA, id: diva2:1305153
Public defence
2019-06-05, P216, NPQ-huset, Svante Arrhenius väg 20, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2019-05-13 Created: 2019-04-15 Last updated: 2019-05-23Bibliographically approved
List of papers
1. Alpha particles and X-rays interact in inducing DNA damage in U2OS cells
Open this publication in new window or tab >>Alpha particles and X-rays interact in inducing DNA damage in U2OS cells
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2017 (English)In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, no 4, p. 400-411Article in journal (Refereed) Published
Abstract [en]

The survivors of atomic bomb explosions in Hiroshima and Nagasaki are monitored for health effect within the Life Span Study (LSS). The LSS results represent the most important source of knowledge about cancer effects of ionizing radiation and they form the basis for the radiation protection system. One uncertainty connected to deriving universal risk factors from these results is related to the problem of mixed radiation qualities. The atomic bomb explosions generated a mixed beam of the sparsely ionizing gamma radiation and densely ionizing neutrons and what is not taken into consideration is the problem of a possible interaction of the two radiation types in inducing biological effects. The existence of such interaction would suggest that the application of risk factors derived from the LSS to predict cancer effects after exposure to pure gamma radiation (such as in the Fukushima prefecture) leads to an overestimation of risk.In order to analyze the possible interaction of radiation types a mixed beam exposure facility was constructed where cells can be exposed to sparsely ionizing X-rays and densely ionizing alpha particles. U2OS cells were used, which are stably transfected with a plasmid coding for the DNA repair gene 53BP1 coupled to a gene coding for the green fluorescent protein GFP. Induction and repair of DNA damage which are known to be related to cancer induction were analyzed. The results suggest that alpha particles and X-rays interact, leading to cellular, and possibly cancer effects not predictable based on assuming simple additivity of the individual mixed beam components.

Keywords
Mixed beam, radiation, DNA damage, Double srtand breaks, 53BP1, alpha particles, X-rays
National Category
Cell Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-145502 (URN)10.1667/RR14803.1 (DOI)000412676400004 ()
Funder
Swedish Radiation Safety Authority
Available from: 2017-08-07 Created: 2017-08-07 Last updated: 2019-04-15Bibliographically approved
2. Simultaneous induction of dispersed and clustered DNA lesions compromises DNA damage response in human peripheral blood lymphocytes
Open this publication in new window or tab >>Simultaneous induction of dispersed and clustered DNA lesions compromises DNA damage response in human peripheral blood lymphocytes
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 10, article id e0204068Article in journal (Refereed) Published
Abstract [en]

Due to its ability to induce DNA damage in a space and time controlled manner, ionising radiation is a unique tool for studying the mechanisms of DNA repair. The biological effectiveness of ionising radiation is related to the ionisation density which is defined by the linear energy transfer (LET). Alpha particles are characterised by high LET, while X-rays by low LET values. An interesting question is how cells react when exposed to a mixed beam of high and low LET radiation. In an earlier study carried out with human peripheral blood lymphocytes (PBL) we could demonstrate that alpha radiation X-rays interact in producing more chromosomal aberrations than expected based on additivity. The aim of the present investigation was to look at the mechanism of the interaction, especially with respect to the question if it is due to an augmented level of initial damage or impaired DNA repair. PBL were exposed to various doses of alpha particles, X-rays and mixed beams. DNA damage and the kinetics of damage repair was quantified by the alkaline comet assay. The levels of phosphorylated, key DNA damage response (DDR) proteins ATM, p53 and DNA-PK were measured by Western blotting and mRNA levels of 6 damage-responsive genes were measured by qPCR. Alpha particles and X-rays interact in inducing DNA damage above the level predicted by assuming additivity and that the repair of damage occurs with a delay. The activation levels of DDR proteins and mRNA levels of the studied genes were highest in cells exposed to mixed beams. The results substantiate the idea that exposure to mixed beams presents a challenge for the cellular DDR system.

National Category
Biological Sciences
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-162898 (URN)10.1371/journal.pone.0204068 (DOI)000448823700008 ()30379881 (PubMedID)
Available from: 2018-12-20 Created: 2018-12-20 Last updated: 2019-04-17Bibliographically approved
3. Hypothermia modulates the DNA damage response to ionizing radiation in human peripheral blood lymphocytes
Open this publication in new window or tab >>Hypothermia modulates the DNA damage response to ionizing radiation in human peripheral blood lymphocytes
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2018 (English)In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 94, no 6, p. 551-557Article in journal (Refereed) Published
Abstract [en]

Purpose: Low temperature at exposure has been shown to act in a radioprotective manner at the level of cytogenetic damage. It was suggested to be due to an effective transformation of DNA damage to chromosomal damage at low temperature. The purpose of the study was to analyze the kinetics of aberration formation during the first hours after exposing human peripheral blood lymphocytes to ionizing radiation at 0.8 degrees C and 37 degrees C.Materials and methods: To this end, we applied the technique of premature chromosome condensation. In addition, DNA damage response was analyzed by measuring the levels of phosphorylated DNA damage responsive proteins ATM, DNA-PK and p53 and mRNA levels of the radiation-responsive genes BBC3, FDXR, GADD45A, XPC, MDM2 and CDKN1A.Results: A consistently lower frequency of chromosomal breaks was observed in cells exposed at 0.8 degrees C as compared to 37 degrees C already after 30minutes postexposure. This effect was accompanied by elevated levels of phosphorylated ATM and DNA-PK proteins and a reduced immediate level of phosphorylated p53 and of the responsive genes.Conclusions: Low temperature at exposure appears to promote DNA repair leading to reduced transformation of DNA damage to chromosomal aberrations.

Keywords
Hypothermia, temperature, premature chromosome condensation, chromosome aberrations, DNA damage response
National Category
Biological Sciences
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-158216 (URN)10.1080/09553002.2018.1466206 (DOI)000433973000004 ()29668347 (PubMedID)
Available from: 2018-07-25 Created: 2018-07-25 Last updated: 2019-04-17Bibliographically approved

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