Correlation between cellular radiosensitivity and non-repaired double-strand breaks studied in nine mammalian cell lines

Dikomey, Ekkehard; Dahm-Daphi, Jochen; Brammer, I.; Martensen, R; Kaina, Bernd

doi:10.1080/095530098142365

Cited by 136 publications

(20 citation statements)

References 49 publications

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“…Previous studies showed that radio sensitivity correlates with the number of DSB remaining after 24 hours (46). Radio-sensitive tumor cell lines and xenografts retain more γH2AX foci 24 hours after IR (47).…”

Section: Discussionmentioning

confidence: 98%

p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression

et al. 2013

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Constitutive heterochromatin is important for maintaining chromosome stability but also delays the repair of DNA double strand breaks (DSB). DSB repair in complex mammalian genomes involves a fast phase (2–6 hrs) where most of the breaks are rapidly repaired, and a slow phase (up to 24 hrs) where the remaining damages in heterochromatin are repaired. We found that p53 deficiency delays the slow phase DNA repair after ionizing irradiation. P53 deficiency prevents down regulation of histone H3K9 trimethylation at pericentric heterochromatin after DNA damage. Moreover, p53 directly induces expression of the H3 K9 demethylase JMJD2b through promoter binding. P53 activation also indirectly down regulates expression of the H3 K9 methytransferase SUV39H1. Depletion of JMJD2b or sustained expression of SUV39H1 delays the repair of heterochromatin DNA and reduces clonogenic survival after ionizing irradiation. The results suggest that by regulating JMJD2b and SUV39H1 expression, p53 not only controls transcription but also promotes heterochromatin relaxation to accelerate a rate-limiting step in the repair of complex genomes.

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Section: Discussionmentioning

confidence: 98%

p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression

et al. 2013

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“…In particular, DSB will lead to a high lethality of the affected cells (134). At the site of DSB damage, the histone H2AX is phosphorylated (referred to as γ-H2AX) by kinases, such as ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related protein (ATR), resulting in the formation of γ-H2AX foci (130).…”

Section: Molecular and Cellular Mechanisms Underlying The Observedmentioning

confidence: 99%

Cardiovascular diseases related to ionizing radiation: The risk of low-dose exposure (Review)

Baselet

Rombouts

Benotmane

et al. 2016

International Journal of Molecular Medicine

107

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Traditionally, non-cancer diseases are not considered as health risks following exposure to low doses of ionizing radiation. Indeed, non-cancer diseases are classified as deterministic tissue reactions, which are characterized by a threshold dose. It is judged that below an absorbed dose of 100 mGy, no clinically relevant tissue damage occurs, forming the basis for the current radiation protection system concerning non-cancer effects. Recent epidemiological findings point, however, to an excess risk of non-cancer diseases following exposure to lower doses of ionizing radiation than was previously thought. The evidence is the most sound for cardiovascular disease (CVD) and cataract. Due to limited statistical power, the dose-risk relationship is undetermined below 0.5 Gy; however, if this relationship proves to be without a threshold, it may have considerable impact on current low-dose health risk estimates. In this review, we describe the CVD risk related to low doses of ionizing radiation, the clinical manifestation and the pathology of radiation-induced CVD, as well as the importance of the endothelium models in CVD research as a way forward to complement the epidemiological data with the underlying biological and molecular mechanisms.

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“…Lack of any of the core components invariably creates a severe DSB repair defect and substantial sensitivity to ionizing radiation and various DNA damaging drugs like topoisomerase II inhibitors (5–9). Although most of the core components proved biochemically to be essential for the end-joining process, it was acknowledged for many years that cells completely lacking these proteins still rejoin the majority of radiation-induced DSBs (6,10–13). Using chromosomal reporter substrates that specifically monitor end-joining processes, we and others found that Ku-deficient and wild-type yeast and mammalian cells were equally capable of rejoining single I-SceI- and HO-induced breaks (14–18).…”

Section: Introductionmentioning

confidence: 99%

The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies

Mansour

Rhein²,

Dahm-Daphi³

2010

Nucleic Acids Research

169

143

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Non-homologous end-joining (NHEJ), the major repair pathway for DNA double-strand breaks (DSB) in mammalian cells, employs a repertoire of core proteins, the recruitment of which to DSB-ends is Ku-dependent. Lack of either of the core components invariably leads to a repair deficiency. There has been evidence that an alternative end-joining operates in the absence of the core components. We used chromosomal reporter substrates to specifically monitor NHEJ of single I-SceI-induced-DSB for detailed comparison of classical and alternative end-joining. We show that rapid repair of both compatible and non-compatible ends require Ku-protein. In the absence of Ku, cells use a slow but efficient repair mode which experiences increasing sequence-loss with time after DSB induction. Chemical inhibition and PARP1-depletion demonstrated that the alternative end-joining in vivo is completely dependent upon functional PARP1. Furthermore, we show that the requirement for PARP1 depends on the absence of Ku but not on DNA-dependent protein kinase (DNA-PKcs). Extensive sequencing of repair junctions revealed that the alternative rejoining does not require long microhomologies. Together, we show that mammalian cells need Ku for rapid and conservative NHEJ. PARP1-dependent alternative route may partially rescue the deficient repair phenotype presumably at the expense of an enhanced mutation rate.

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Correlation between cellular radiosensitivity and non-repaired double-strand breaks studied in nine mammalian cell lines

Abstract: The results obtained strongly suggest that the number of non-repaired double-strand breaks measured 24h after irradiation can be used as an indicator of cellular radiosensitivity.

Cited by 136 publications

References 49 publications

p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression

p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression

Cardiovascular diseases related to ionizing radiation: The risk of low-dose exposure (Review)

The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies

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