The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Julia L Brumaghim - One of the best experts on this subject based on the ideXlab platform.
-
preventing metal mediated oxidative DNA Damage with selenium compounds
Metallomics, 2011Co-Authors: Erin E Battin, Matthew T Zimmerman, Ria R Ramoutar, Carolyn E Quarles, Julia L BrumaghimAbstract:Copper and iron are two widely studied transition metals associated with hydroxyl radical (˙OH) generation, oxidative Damage, and disease development. Because antioxidants ameliorate metal-mediated DNA Damage, DNA gel electrophoresis assays were used to quantify the ability of ten selenium-containing compounds to inhibit metal-mediated DNA Damage by hydroxyl radical. In the CuI/H2O2 system, selenocystine, selenomethionine, and methyl-selenocysteine inhibit DNA Damage with IC50 values ranging from 3.34 to 25.1 μM. Four selenium compounds also prevent DNA Damage from FeII and H2O2. Additional gel electrophoresis experiments indicate that CuI or FeII coordination is responsible for the selenium antioxidant activity. Mass spectrometry studies show that a 1 : 1 stoichiometry is the most common for iron and copper complexes of the tested compounds, even if no antioxidant activity is observed, suggesting that metal coordination is necessary but not sufficient for selenium antioxidant activity. A majority of the selenium compounds are electroactive, regardless of antioxidant activity, and the glutathione peroxidase activities of the selenium compounds show no correlation to DNA Damage inhibition. Thus, metal binding is a primary mechanism of selenium antioxidant activity, and both the chemical functionality of the selenium compound and the metal ion generating damaging hydroxyl radical significantly affect selenium antioxidant behavior.
-
effects of inorganic selenium compounds on oxidative DNA Damage
Journal of Inorganic Biochemistry, 2007Co-Authors: Ria R Ramoutar, Julia L BrumaghimAbstract:Abstract Exposure of Escherichia coli or mammalian cells to H 2 O 2 results in cell death due to iron-mediated DNA Damage. Since selenium compounds have been examined for their ability to act as antioxidants to neutralize radical species, and inorganic selenium compounds are used to supplement protein mixes, infant formula, and animal feed, determining the effect of these compounds on DNA Damage under conditions of oxidative stress is crucial. In the presence of Fe(II) and H 2 O 2 , the effects of Na 2 SeO 4 , Na 2 SeO 3 , SeO 2 (0.5–5000 μM), and Na 2 Se (0.5–200 μM) on DNA Damage were quantified using gel electrophoresis. Both Na 2 SeO 4 and Na 2 Se have no effect on DNA Damage, whereas SeO 2 inhibits DNA Damage and Na 2 SeO 3 shows antioxidant or pro-oxidant activity depending on H 2 O 2 concentration. Similar electrophoresis experiments with [Fe(EDTA)] 2− (400 μM) and Na 2 SeO 3 or SeO 2 show that metal coordination by the selenium compound is required for antioxidant activity. In light of these results, Na 2 SeO 4 may be safer than Na 2 SeO 3 for nutritional supplements.
Stephen P. Jackson - One of the best experts on this subject based on the ideXlab platform.
-
ubiquitylation neddylation and the DNA Damage response
Open Biology, 2015Co-Authors: Jessica S Brown, Stephen P. JacksonAbstract:Failure of accurate DNA Damage sensing and repair mechanisms manifests as a variety of human diseases, including neurodegenerative disorders, immunodeficiency, infertility and cancer. The accuracy and efficiency of DNA Damage detection and repair, collectively termed the DNA Damage response (DDR), requires the recruitment and subsequent post-translational modification (PTM) of a complex network of proteins. Ubiquitin and the ubiquitin-like protein (UBL) SUMO have established roles in regulating the cellular response to DNA double-strand breaks (DSBs). A role for other UBLs, such as NEDD8, is also now emerging. This article provides an overview of the DDR, discusses our current understanding of the process and function of PTM by ubiquitin and NEDD8, and reviews the literature surrounding the role of ubiquitylation and neddylation in DNA repair processes, focusing particularly on DNA DSB repair.
-
human cell senescence as a DNA Damage response
Mechanisms of Ageing and Development, 2005Co-Authors: T Von Zglinicki, Gabriele Saretzki, J Ladhoff, Dadda F Di Fagagna, Stephen P. JacksonAbstract:Abstract It has been established that telomere-dependent replicative senescence of human fibroblasts is stress-dependent. First, it was shown that telomere shortening, which is a major contributor to telomere uncapping, is stress-dependent to a significant degree. Second, the signalling pathway connecting telomere uncapping and replicative senescence appears to be the same as the one that is activated by DNA Damage: uncapped telomeres activate signalling cascades involving the protein kinases ATM, ATR and, possibly, DNA-PK. Furthermore, phosphorylation of histone H2A.X facilitates the formation of DNA Damage foci around uncapped telomeres, and this in turn activates downstream kinases Chk1 and Chk2 and, eventually, p53. It appears that this signalling pathway has to be maintained in order to keep cells in a senescent state. Thus, cellular senescence can be regarded as a permanently maintained DNA Damage response state. This suggests that antibodies against DNA Damage foci components might be useful markers for senescent cells in vivo.
-
A DNA Damage checkpoint response in telomere-initiated senescence
Nature, 2003Co-Authors: Fabrizio D'adda Di Fagagna, Philip M. Reaper, Lorena Clay-farrace, Philippa Carr, Heike Fiegler, Thomas Von Zglinicki, Gabriele Saretzki, Nigel P Carter, Stephen P. JacksonAbstract:Most human somatic cells can undergo only a limited number of population doublings in vitro. This exhaustion of proliferative potential, called senescence, can be triggered when telomeres--the ends of linear chromosomes-cannot fulfil their normal protective functions. Here we show that senescent human fibroblasts display molecular markers characteristic of cells bearing DNA double-strand breaks. These markers include nuclear foci of phosphorylated histone H2AX and their co-localization with DNA repair and DNA Damage checkpoint factors such as 53BP1, MDC1 and NBS1. We also show that senescent cells contain activated forms of the DNA Damage checkpoint kinases CHK1 and CHK2. Furthermore, by chromatin immunoprecipitation and whole-genome scanning approaches, we show that the chromosome ends of senescent cells directly contribute to the DNA Damage response, and that uncapped telomeres directly associate with many, but not all, DNA Damage response proteins. Finally, we show that inactivation of DNA Damage checkpoint kinases in senescent cells can restore cell-cycle progression into S phase. Thus, we propose that telomere-initiated senescence reflects a DNA Damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.
Francesca Rossiello - One of the best experts on this subject based on the ideXlab platform.
-
DNA Damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA Damage response rnas
Nature Communications, 2017Co-Authors: Francesca Rossiello, Julio Aguado, Sara Sepe, Fabio Iannelli, Quan Nguyen, Sethuramasundaram Pitchiaya, Piero Carninci, Fabrizio Dadda Di FagagnaAbstract:The DNA Damage response (DDR) is a set of cellular events that follows the generation of DNA Damage. Recently, site-specific small non-coding RNAs, also termed DNA Damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Dysfunctional telomeres activate DDR in ageing, cancer and an increasing number of identified pathological conditions. Here we show that, in mammals, telomere dysfunction induces the transcription of telomeric DDRNAs (tDDRNAs) and their longer precursors from both DNA strands. DDR activation and maintenance at telomeres depend on the biogenesis and functions of tDDRNAs. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues. In summary, these results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs. The DNA Damage response (DDR) involves site-specific small non-coding RNAs. Here the authors show that telomere dysfunction induces transcription of telomeric DNA Damage response RNAs that are necessary for DDR activation, which can be specifically muted by antisense inhibitory oligonucleotides.
-
Telomeric DNA Damage is irreparable and causes persistent DNA-Damage-response activation
Nature Cell Biology, 2012Co-Authors: Matteo Fumagalli, Michela Clerici, Jessica M. Kaplunov, Miryana Dobreva, Valentina Matti, Francesca Rossiello, Serena Barozzi, Gabriele Bucci, Davide Cittaro, Christian M. BeausejourAbstract:The DNA-Damage response (DDR) arrests cell-cycle progression until Damage is removed. DNA-Damage-induced cellular senescence is associated with persistent DDR. The molecular bases that distinguish transient from persistent DDR are unknown. Here we show that a large fraction of exogenously induced persistent DDR markers is associated with telomeric DNA in cultured cells and mammalian tissues. In yeast, a chromosomal DNA double-strand break next to a telomeric sequence resists repair and impairs DNA ligase 4 recruitment. In mammalian cells, ectopic localization of telomeric factor TRF2 next to a double-strand break induces persistent DNA Damage and DDR. Linear, but not circular, telomeric DNA or scrambled DNA induces a prolonged checkpoint in normal cells. In terminally differentiated tissues of old primates, DDR markers accumulate at telomeres that are not critically short. We propose that linear genomes are not uniformly reparable and that telomeric DNA tracts, if Damaged, are irreparable and trigger persistent DDR and cellular senescence.
Christian M. Beausejour - One of the best experts on this subject based on the ideXlab platform.
-
Telomeric DNA Damage is irreparable and causes persistent DNA-Damage-response activation
Nature Cell Biology, 2012Co-Authors: Matteo Fumagalli, Michela Clerici, Jessica M. Kaplunov, Miryana Dobreva, Valentina Matti, Francesca Rossiello, Serena Barozzi, Gabriele Bucci, Davide Cittaro, Christian M. BeausejourAbstract:The DNA-Damage response (DDR) arrests cell-cycle progression until Damage is removed. DNA-Damage-induced cellular senescence is associated with persistent DDR. The molecular bases that distinguish transient from persistent DDR are unknown. Here we show that a large fraction of exogenously induced persistent DDR markers is associated with telomeric DNA in cultured cells and mammalian tissues. In yeast, a chromosomal DNA double-strand break next to a telomeric sequence resists repair and impairs DNA ligase 4 recruitment. In mammalian cells, ectopic localization of telomeric factor TRF2 next to a double-strand break induces persistent DNA Damage and DDR. Linear, but not circular, telomeric DNA or scrambled DNA induces a prolonged checkpoint in normal cells. In terminally differentiated tissues of old primates, DDR markers accumulate at telomeres that are not critically short. We propose that linear genomes are not uniformly reparable and that telomeric DNA tracts, if Damaged, are irreparable and trigger persistent DDR and cellular senescence.
Jan Lammerding - One of the best experts on this subject based on the ideXlab platform.
-
nuclear deformation causes DNA Damage by increasing replication stress
Current Biology, 2021Co-Authors: Pragya Shah, Svea Cheng, Chad M Hobson, Marshall J Colville, Matthew J Paszek, Richard Superfine, Jan LammerdingAbstract:Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA Damage. The molecular mechanisms responsible for the confined migration-induced DNA Damage remain incompletely understood. Although in some cell lines, DNA Damage is closely associated with nuclear envelope rupture, we show that, in others, mechanical deformation of the nucleus is sufficient to cause DNA Damage, even in the absence of nuclear envelope rupture. This deformation-induced DNA Damage, unlike nuclear-envelope-rupture-induced DNA Damage, occurs primarily in S/G2 phase of the cell cycle and is associated with replication forks. Nuclear deformation, resulting from either confined migration or external cell compression, increases replication stress, possibly by increasing replication fork stalling, providing a molecular mechanism for the deformation-induced DNA Damage. Thus, we have uncovered a new mechanism for mechanically induced DNA Damage, linking mechanical deformation of the nucleus to DNA replication stress. This mechanically induced DNA Damage could not only increase genomic instability in metastasizing cancer cells but could also cause DNA Damage in non-migrating cells and tissues that experience mechanical compression during development, thereby contributing to tumorigenesis and DNA Damage response activation.
-
nuclear deformation causes DNA Damage by increasing replication stress
bioRxiv, 2020Co-Authors: Pragya Shah, Svea Cheng, Chad M Hobson, Marshall J Colville, Matthew J Paszek, Richard Superfine, Jan LammerdingAbstract:Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA Damage. The molecular mechanisms responsible for the confined migration-induced DNA Damage remain incompletely understood. While in some cell lines, DNA Damage is closely associated with nuclear envelope rupture, we show that in others, mechanical deformation of the nucleus is sufficient to cause DNA Damage, even in the absence of nuclear envelope rupture. This deformation-induced DNA Damage, unlike nuclear envelope rupture-induced DNA Damage, occurs primarily in S/G2 phase of the cell cycle and is associated with stalled replication forks. Nuclear deformation, resulting from either confined migration or external cell compression, increases replication fork stalling and replication stress, providing a molecular mechanism for the deformation-induced DNA Damage. Thus, we have uncovered a new mechanism for mechanically induced DNA Damage, linking mechanical deformation of the nucleus to DNA replication stress. This mechanically induced DNA Damage could not only increase genomic instability in metastasizing cancer cells, but could also cause DNA Damage in non-migrating cells and tissues that experience mechanical compression during development, thereby contributing to tumorigenesis and DNA Damage response activation.
