DNA double-strand break repair

Featherstone, Carol; Jackson, Stephen

doi:10.1016/s0960-9822(00)80005-6

Cited by 159 publications

(101 citation statements)

References 4 publications

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“…The G 2 cell-cycle checkpoint after DNA damage helps ensure the integrity of the genome (34,35). Previous work showed that nitroxide treatment led to an increased number of cells in the G 2 /M phase of the cell cycle (36).…”

Section: Hemi-gs-tempo 5-125 Prolonged γ-Irradiation-induced G 2 /M Pmentioning

confidence: 99%

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

Jiang¹,

Belikova²,

Hoye³

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose-To evaluate the in vitro radioprotective effect of the mitochondria-targeted hemigramicidin S-conjugated 4-amino-2,2,6,6-tetramethyl-piperidine-N-oxyl (hemi-GS-TEMPO) 5-125 in γ-irradiated mouse embryonic cells and adenovirus-12 SV40 hybrid virus transformed human bronchial epithelial cells BEAS-2B and explore the mechanisms involved in its radioprotective effect.Methods and Materials-Cells were incubated with 5-125 before (10 minutes) or after (1 hour) γ-irradiation. Superoxide generation was determined by using dihydroethidium assay, and lipid oxidation was quantitated by using a fluorescence high-performance liquid chromatography-based Amplex Red assay. Apoptosis was characterized by evaluating the accumulation of cytochrome c in the cytosol and externalization of phosphatidylserine on the cell surface. Cell survival was measured by means of a clonogenic assay.Results-Treatment (before and after irradiation) of cells with 5-125 at low concentrations (5, 10, and 20 μM) effectively suppressed γ-irradiation-induced superoxide generation, cardiolipin oxidation, and delayed irradiation-induced apoptosis, evaluated by using cytochrome c release and phosphatidylserine externalization. Importantly, treatment with 5-125 increased the clonogenic survival rate of γ-irradiated cells. In addition, 5-125 enhanced and prolonged γ-irradiation-induced G 2 /M phase arrest.Conclusions-Radioprotection/mitigation by hemi-GS-TEMPO likely is caused by its ability to act as an electron scavenger and prevent superoxide generation, attenuate cardiolipin oxidation in mitochondria, and hence prevent the release of proapoptotic factors from mitochondria. Other mechanisms, including cell-cycle arrest at the G 2 /M phase, may contribute to the protection.

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Section: Hemi-gs-tempo 5-125 Prolonged γ-Irradiation-induced G 2 /M Pmentioning

confidence: 99%

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

Jiang¹,

Belikova²,

Hoye³

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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“…[1][2][3][4][5] One of the proteins involved in recognizing a particular type of DNA damage, DNA double-strand breaks (DSBs), is p53 Binding Protein 1 (53BP1), a protein that participates both in checkpoint activation by inducing cell cycle arrest and in DNA DSB repair by stimulating non-homologous end joining. [6][7][8][9][10][11][12][13][14][15] 53BP1 contains a tandem tudor domain, between amino acids 1485-1602, which is critical for recruitment to sites of DNA DSBs.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

et al. 2015

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The mammalian E3 ubiquitin ligases RNF8 and RNF168 facilitate recruitment of the DNA damage response protein 53BP1 to sites of DNA double-strand breaks (DSBs). The mechanism involves recruitment of RNF8, followed by recruitment of RNF168, which ubiquitinates histones H2A/H2AX on K15. 53BP1 then binds to nucleosomes at sites of DNA DSBs by recognizing, in addition to methyl marks, histone H2A/H2AX ubiquitinated on K15. We report here that expressing H2AX fusion proteins with N-terminal bulky moieties can rescue 53BP1 recruitment to sites of DNA DSBs in cells lacking RNF8 or RNF168 or in cells treated with proteasome inhibitors, in which histone ubiquitination at sites of DNA DSBs is compromised. The rescue required S139 at the C-terminus of the H2AX fusion protein and was occasionally accompanied by partial rescue of ubiquitination at sites of DNA DSBs. We conclude that recruitment of 53BP1 to sites of DNA DSBs is possible in the absence of RNF8 or RNF168, but still dependent on chromatin ubiquitination.

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“…The former requires genes in the RAD52 epistasis group and relies on extensive homology between the damaged DNA and an undamaged partner [sister chromatid or homologous chromosome (8)]. By contrast, NHEJ requires little or no homology between the recombining molecules (9). Key components of the NHEJ machinery in mammals include the Ku70͞Ku80 heterodimer and the Ligase IV͞XRCC4 complex, all of which have functional counterparts in yeast [Yku70p, Yku80p, Dnl4p, and Lif1p, respectively (10)].…”

mentioning

confidence: 99%

Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair

Jazayeri

McAinsh

Jackson

2004

Proc. Natl. Acad. Sci. U.S.A.

148

114

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There are two main pathways in eukaryotic cells for the repair of DNA double-strand breaks: homologous recombination and nonhomologous end joining. Because eukaryotic genomes are packaged in chromatin, these pathways are likely to require the modulation of chromatin structure. One way to achieve this is by the acetylation of lysine residues on the N-terminal tails of histones. Here we demonstrate that Sin3p and Rpd3p, components of one of the predominant histone deacetylase complexes of Saccharomyces cerevisiae, are required for efficient nonhomologous end joining. We also show that lysine 16 of histone H4 becomes deacetylated in the proximity of a chromosomal DNA doublestrand break in a Sin3p-dependent manner. Taken together, these results define a role for the Sin3p͞Rpd3p complex in the modulation of DNA repair.I n eukaryotic cells, the genome is compacted into chromatin.The basic unit of chromatin is the nucleosome, which is composed of the conserved core histones H2A, H2B, H3, and H4. The structure of nucleosomal DNA is further compacted by a range of other factors, including proteins such as the linker histone H1 that binds to DNA between the nucleosome repeats (1). Various DNA-templated processes such as transcription, replication, and DNA repair take place in the context of chromatin and so must involve the manipulation of nucleosomes. One way to achieve this is through the reversible acetylation, phosphorylation, ubiquitination, or ADP-ribosylation of the histone tails that extend to the accessible surface of the nucleosome core particle (2). It has been proposed that combinations of these modifications create a ''histone code'' that is recognized by other proteins to bring about specific downstream events (3).The most extensive body of data has been accumulated for the effect of nucleosome modifications in transcription (4). However, there is growing evidence that there is cross-talk between chromatin and DNA damage response and repair pathways. This is particularly well established for nucleotide excision repair (NER), in which several chromatin remodeling and modification factors have been implicated (ref. 5 and references therein). As discussed further below, there is also evidence for the importance of chromatin modification in the repair of DNA doublestrand breaks (DSBs), which are generated by ionizing radiation and a range of chemotherapeutic agents. Given the highly recombinogenic and cytotoxic nature of such lesions (6, 7), the impact of chromatin on DSB repair is likely to be of considerable biological importance.There are two principle mechanisms for the repair of DNA DSBs: homologous recombination (HR) and nonhomologous end joining (NHEJ). The former requires genes in the RAD52 epistasis group and relies on extensive homology between the damaged DNA and an undamaged partner [sister chromatid or homologous chromosome (8)]. By contrast, NHEJ requires little or no homology between the recombining molecules (9). Key components of the NHEJ machinery in mammals include the Ku70͞Ku80 heterodimer an...

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DNA double-strand break repair

Cited by 159 publications

References 4 publications

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair

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