The link between cell-cycle dependent radiosensitivity and repair pathways: A model based on the local, sister-chromatid conformation dependent switch between NHEJ and HR

Hufnagl, Antonia; Herr, Lisa; Friedrich, Thomas; Durante, Marco; Taucher-Scholz, G.; Scholz, M.

doi:10.1016/j.dnarep.2015.01.002

Cited by 37 publications

(38 citation statements)

References 58 publications

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“…It is now generally accepted that high-LET radiation induces complex clustered damage to DNA, particularly complex double-stranded breaks (DSBs) [22–25], which are less repairable by either non-homologous end-joining or the homologous recombination pathway [26]. Throughout this paper, ‘clustered damage’ to DNA is intended to refer only to damage at the nanometer level of the DNA molecule, mostly extending over not more than one or two helical turns of the DNA, in accordance with the original usage of the term in the references cited.…”

Section: Resultsmentioning

confidence: 99%

Dependence and independence of survival parameters on linear energy transfer in cells and tissues

Andō¹,

Goodhead²

2016

Journal of Radiation Research

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Carbon-ion radiotherapy has been used to treat more than 9000 cancer patients in the world since 1994. Spreading of the Bragg peak is necessary for carbon-ion radiotherapy, and is designed based on the linear–quadratic model that is commonly used for photon therapy. Our recent analysis using in vitro cell kills and in vivo mouse tissue reaction indicates that radiation quality affects mainly the alpha terms, but much less the beta terms, which raises the question of whether this is true in other biological systems. Survival parameters alpha and beta for 45 in vitro mammalian cell lines were obtained by colony formation after irradiation with carbon ions, fast neutrons and X-rays. Relationships between survival parameters and linear energy transfer (LET) below 100 keV/μm were obtained for 4 mammalian cell lines. Mouse skin reaction and tumor growth delay were measured after fractionated irradiation. The Fe-plot provided survival parameters of the tissue reactions. A clear separation between X-rays and high-LET radiation was observed for alpha values, but not for beta values. Alpha values/terms increased with increasing LET in any cells and tissues studied, while beta did not show a systematic change. We have found a puzzle or contradiction in common interpretations of the linear-quadratic model that causes us to question whether the model is appropriate for interpreting biological effectiveness of high-LET radiation up to 500 keV/μm, probably because of inconsistency in the concept of damage interaction. A repair saturation model proposed here was good enough to fit cell kill efficiency by radiation of wide-ranged LET. A model incorporating damage complexity and repair saturation would be suitable for heavy-ion radiotherapy.

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Section: Resultsmentioning

confidence: 99%

Dependence and independence of survival parameters on linear energy transfer in cells and tissues

Andō¹,

Goodhead²

2016

Journal of Radiation Research

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“…In this study, DNA damage was induced with four different DNA DSB-producing mechanisms. The high-energy γ-irradiation breaks the DNA strands directly and mainly involves the NHEJ repair pathway [15,16]. It is not fully confirmed whether MMS directly induces DSBs, but it stalls DNA replication and HR is involved in the repair of stalled replication forks [17].…”

Section: Discussionmentioning

confidence: 99%

Extracellular ATP protects endothelial cells against DNA damage

Aho

Helenius

Vattulainen-Collanus

et al. 2016

Purinergic Signalling

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Cell damage can lead to rapid release of ATP to extracellular space resulting in dramatic change in local ATP concentration. Evolutionary, this has been considered as a danger signal leading to adaptive responses in adjacent cells.Our aim was to demonstrate that elevated extracellular ATP or inhibition of ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39) activity could be used to increase tolerance against DNA-damaging conditions. Human endothelial cells, with increased extracellular ATP concentration in cell proximity, were more resistant to irradiation or chemically induced DNA damage evaluated with the DNA damage markers γH2AX and phosphorylated p53. In our rat models of DNA damage, inhibiting CD39-driven ATP hydrolysis with POM-1 protected the heart and lung tissues against chemically induced DNA damage. Interestingly, the phenomenon could not be replicated in cancer cells. Our results show that transient increase in extracellular ATP can promote resistance to DNA damage.

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“…This phenomenon is seen in another radiobiological tenet, namely reassort ment, which enables fractionation to preferentially kill proliferating cells within radiosensitive cell-cycle phases. The link between HR and the S/G2 cell-cycle phase 28,29 has been attributed largely to a requirement for cyclin-dependent kinase 1 (CDK1) for DNA resection ( Figure 1). 30 CDK1 activates HR by phosphorylating key recombination factors, and phosphorylates the XRCC4-like factor (XLF; also known as Cernunnos) to downregulate NHEJ, at least in yeast.…”

Section: Targeting Dna Damage and Repairmentioning

confidence: 99%

Opportunities and challenges of radiotherapy for treating cancer

2015

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The past 20 years have seen dramatic changes in the delivery of radiation therapy, but the impact of radiobiology on the clinic has been far less substantial. A major consideration in the use of radiotherapy has been on how best to exploit differences between the tumour and host tissue characteristics, which in the past has been achieved empirically by radiation-dose fractionation. New advances are uncovering some of the mechanistic processes that underlie this success story. In this Review, we focus on how these processes might be targeted to improve the outcome of radiotherapy at the individual patient level. This approach would seem a more productive avenue of treatment than simply trying to increase the radiation dose delivered to the tumour.

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The link between cell-cycle dependent radiosensitivity and repair pathways: A model based on the local, sister-chromatid conformation dependent switch between NHEJ and HR

Cited by 37 publications

References 58 publications

Dependence and independence of survival parameters on linear energy transfer in cells and tissues

Dependence and independence of survival parameters on linear energy transfer in cells and tissues

Extracellular ATP protects endothelial cells against DNA damage

Opportunities and challenges of radiotherapy for treating cancer

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