Vacuum-UV induced DNA strand breaks – influence of the radiosensitizers 5-bromouracil and 8-bromoadenine

2019 ◽  
Vol 21 (4) ◽  
pp. 1972-1979 ◽  
Author(s):  
Stefanie Vogel ◽  
Kenny Ebel ◽  
Christian Heck ◽  
Robin M. Schürmann ◽  
Aleksandar R. Milosavljević ◽  
...  
Keyword(s):  
Strand Break ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Dna Strand ◽  
Vacuum Uv ◽  
Break Yield

VUV induced strand breaks in oligonucleotides modified by 5-Bromouracil (5-BrU) and 8-Bromoadenine (8-BrA) is quantified. While 5-BrU is an efficient photosensitizer, 8-BrA does not increase the strand break yield.

Vacuum‐UV and Low‐Energy Electron‐Induced DNA Strand Breaks – Influence of the DNA Sequence and Substrate

ChemPhysChem ◽  
2019 ◽  
Vol 20 (6) ◽  
pp. 823-830 ◽  
Author(s):  
Stefanie Vogel ◽  
Kenny Ebel ◽  
Robin M. Schürmann ◽  
Christian Heck ◽  
Till Meiling ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Dna Strand Breaks ◽  
Low Energy ◽  
Energy Electron ◽  
Strand Breaks ◽  
Low Energy Electron ◽  
Dna Strand ◽  
Vacuum Uv

scholarly journals Mechanistic insight into the role of Poly(ADP-ribosyl)ation in DNA topology modulation and response to DNA damage

Mutagenesis ◽  
2019 ◽  
Vol 35 (1) ◽  
pp. 107-118
Author(s):  
Bakhyt T Matkarimov ◽  
Dmitry O Zharkov ◽  
Murat K Saparbaev
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genotoxic Stress ◽  
Strand Break ◽  
Dna Supercoiling ◽  
Dna Strand Breaks ◽  
Chromosomal Dna ◽  
Dna Breaks ◽  
Strand Breaks ◽  
Dna Strand

Abstract Genotoxic stress generates single- and double-strand DNA breaks either through direct damage by reactive oxygen species or as intermediates of DNA repair. Failure to detect and repair DNA strand breaks leads to deleterious consequences such as chromosomal aberrations, genomic instability and cell death. DNA strand breaks disrupt the superhelical state of cellular DNA, which further disturbs the chromatin architecture and gene activity regulation. Proteins from the poly(ADP-ribose) polymerase (PARP) family, such as PARP1 and PARP2, use NAD+ as a substrate to catalyse the synthesis of polymeric chains consisting of ADP-ribose units covalently attached to an acceptor molecule. PARP1 and PARP2 are regarded as DNA damage sensors that, upon activation by strand breaks, poly(ADP-ribosyl)ate themselves and nuclear acceptor proteins. Noteworthy, the regularly branched structure of poly(ADP-ribose) polymer suggests that the mechanism of its synthesis may involve circular movement of PARP1 around the DNA helix, with a branching point in PAR corresponding to one complete 360° turn. We propose that PARP1 stays bound to a DNA strand break end, but rotates around the helix displaced by the growing poly(ADP-ribose) chain, and that this rotation could introduce positive supercoils into damaged chromosomal DNA. This topology modulation would enable nucleosome displacement and chromatin decondensation around the lesion site, facilitating the access of DNA repair proteins or transcription factors. PARP1-mediated DNA supercoiling can be transmitted over long distances, resulting in changes in the high-order chromatin structures. The available structures of PARP1 are consistent with the strand break-induced PAR synthesis as a driving force for PARP1 rotation around the DNA axis.

scholarly journals Cover Feature: Vacuum‐UV and Low‐Energy Electron‐Induced DNA Strand Breaks – Influence of the DNA Sequence and Substrate (ChemPhysChem 6/2019)

ChemPhysChem ◽  
2019 ◽  
Vol 20 (6) ◽  
pp. 788-788
Author(s):  
Stefanie Vogel ◽  
Kenny Ebel ◽  
Robin M. Schürmann ◽  
Christian Heck ◽  
Till Meiling ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Dna Strand Breaks ◽  
Low Energy ◽  
Energy Electron ◽  
Strand Breaks ◽  
Low Energy Electron ◽  
Dna Strand ◽  
Vacuum Uv

scholarly journals Structural chromosome abnormalities, increased DNA strand breaks and DNA strand break repair deficiency in dermal fibroblasts from old female human donors

Aging ◽  
2015 ◽  
Vol 7 (2) ◽  
pp. 110-122 ◽  
Author(s):  
Faiza Kalfalah ◽  
Sabine Seggewiß ◽  
Regina Walter ◽  
Julia Tigges ◽  
María Moreno-Villanueva ◽  
...  
Keyword(s):  
Strand Break ◽  
Dna Strand Breaks ◽  
Dermal Fibroblasts ◽  
Chromosome Abnormalities ◽  
Strand Breaks ◽  
Dna Strand Break ◽  
Repair Deficiency ◽  
Structural Chromosome ◽  
Break Repair ◽  
Dna Strand

scholarly journals Amyotrophic lateral sclerosis-associated TDP-43 mutation Q331K prevents nuclear translocation of XRCC4-DNA ligase 4 complex and is linked to genome damage-mediated neuronal apoptosis

2019 ◽  
Vol 28 (15) ◽  
pp. 2459-2476 ◽  
Author(s):  
Erika N Guerrero ◽  
Joy Mitra ◽  
Haibo Wang ◽  
Suganya Rangaswamy ◽  
Pavana M Hegde ◽  
...  
Keyword(s):  
Neuronal Apoptosis ◽  
Nuclear Translocation ◽  
Strand Break ◽  
Dna Strand Breaks ◽  
Dna Ligase ◽  
Strand Breaks ◽  
Genome Damage ◽  
Dna Strand ◽  
Mutant Cells ◽  
Lateral Sclerosis

Abstract Dominant mutations in the RNA/DNA-binding protein TDP-43 have been linked to amyotrophic lateral sclerosis (ALS). Here, we screened genomic DNA extracted from spinal cord specimens of sporadic ALS patients for mutations in the TARDBP gene and identified a patient specimen with previously reported Q331K mutation. The patient spinal cord tissue with Q331K mutation showed accumulation of higher levels of DNA strand breaks and the DNA double-strand break (DSB) marker γH2AX, compared to age-matched controls, suggesting a role of the Q331K mutation in genome-damage accumulation. Using conditional SH-SY5Y lines ectopically expressing wild-type (WT) or Q331K-mutant TDP-43, we confirmed the increased cytosolic sequestration of the poly-ubiquitinated and aggregated form of mutant TDP-43, which correlated with increased genomic DNA strand breaks, activation of the DNA damage response factors phospho-ataxia-telangiectasia mutated (ATM), phospho-53BP1, γH2AX and neuronal apoptosis. We recently reported the involvement of WT TDP-43 in non-homologous end joining (NHEJ)-mediated DSB repair, where it acts as a scaffold for the recruitment of XRCC4-DNA ligase 4 complex. Here, the mutant TDP-43, due to its reduced interaction and enhanced cytosolic mislocalization, prevented the nuclear translocation of XRCC4-DNA ligase 4. Consistently, the mutant cells showed significantly reduced DNA strand break sealing activity and were sensitized to DNA-damaging drugs. In addition, the mutant cells showed elevated levels of reactive oxygen species, suggesting both dominant negative and loss-of-function effects of the mutation. Together, our study uncovered an association of sporadic Q331K mutation with persistent genome damage accumulation due to both damage induction and repair defects.

scholarly journals Inhibition of poly(ADP-ribose) polymerase activity affects its subcellular localization and DNA strand break rejoining.

2009 ◽  
Vol 56 (2) ◽  
Author(s):  
Nadezhda I Ryabokon ◽  
Artur Cieślar-Pobuda ◽  
Joanna Rzeszowska-Wolny
Keyword(s):  
Dna Repair ◽  
Parp Inhibitor ◽  
Strand Break ◽  
Parp Inhibitors ◽  
Polymerase Activity ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Dna Strand Break ◽  
Parp Activity ◽  
Dna Strand

Poly(ADP-ribose) polymerase (PARP) plays a crucial role in DNA repair. Modulation of its activity by stimulation or inhibition is considered as a potentially important strategy in clinical practice, especially to sensitize tumor cells to chemo- and radiotherapy through inhibition of DNA repair. Here we studied the effect of the three PARP inhibitors, 5-iodo-6-amino-benzopyrone (INH(2)BP), 1,5-isoquinolinediol (1,5-dihydroxyisoquinolinediol (1,5-IQD) and 8-hydroxy-2-methylquinazolin-4-[3H]one (NU1025), and for two of them the efficiency in slowing the rejoining of DNA strand breaks induced by H(2)O(2) was compared. Inhibition of PARP changed its intranuclear localization markedly; cells exposed to the inhibitor NU1025 showed a significant tendency to accumulate PARP in large foci, whereas in untreated cells its distribution was more uniform. The speed and efficiency of rejoining of H(2)O(2)-induced DNA strand breaks were lower in cells incubated with a PARP inhibitor, and the kinetics of rejoining were modulated in a different manner by each inhibitor. At a concentration of 100 microM the efficiency of the inhibitors could be ranked in the order NU1025 > IQD > INH(2)BP. The two first compounds were able to decrease the overall PARP activity below the level detected in control cells, while INH(2)BP showed up to 40% PARP activity after exposure to H(2)O(2).

scholarly journals APLF (C2orf13) Is a Novel Human Protein Involved in the Cellular Response to Chromosomal DNA Strand Breaks

2007 ◽  
Vol 27 (10) ◽  
pp. 3793-3803 ◽  
Author(s):  
Natasha Iles ◽  
Stuart Rulten ◽  
Sherif F. El-Khamisy ◽  
Keith W. Caldecott
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
Strand Break ◽  
Dna Strand Breaks ◽  
Double Strand Break Repair ◽  
Chromosomal Dna ◽  
Fha Domain ◽  
Strand Breaks ◽  
Break Repair ◽  
Dna Strand

ABSTRACT Aprataxin and polynucleotide kinase (PNK) are DNA end processing factors that are recruited into the DNA single- and double-strand break repair machinery through phosphorylation-specific interactions with XRCC1 and XRCC4, respectively. These interactions are mediated through a divergent class of forkhead-associated (FHA) domain that binds to peptide sequences in XRCC1 and XRCC4 that are phosphorylated by casein kinase 2 (CK2). Here, we identify the product of the uncharacterized open reading frame C2orf13 as a novel member of this FHA domain family of proteins and we denote this protein APLF (aprataxin- and PNK-like factor). We show that APLF interacts with XRCC1 in vivo and in vitro in a manner that is stimulated by CK2. Yeast two-hybrid analyses suggest that APLF also interacts with the double-strand break repair proteins XRCC4 and XRCC5 (Ku86). We also show that endogenous and yellow fluorescent protein-tagged APLF accumulates at sites of H2O2 or UVA laser-induced chromosomal DNA damage and that this is achieved through at least two mechanisms: one that requires the FHA domain-mediated interaction with XRCC1 and a second that is independent of XRCC1 but requires a novel type of zinc finger motif located at the C terminus of APLF. Finally, we demonstrate that APLF is phosphorylated in a DNA damage- and ATM-dependent manner and that the depletion of APLF from noncycling human SH-SY5Y neuroblastoma cells reduces rates of chromosomal DNA strand break repair following ionizing radiation. These data identify APLF as a novel component of the cellular response to DNA strand breaks in human cells.

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