Faculty Opinions recommendation of DNA damage induces nuclear actin filament assembly by Formin -2 and Spire-½ that promotes efficient DNA repair. [corrected].

2015 ◽  
Author(s):  
Edward Egelman
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Actin Filament ◽  
Nuclear Actin ◽  
Filament Assembly

scholarly journals DNA damage induces nuclear actin filament assembly by Formin-2 and Spire-1/2 that promotes efficient DNA repair

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Brittany J Belin ◽  
Terri Lee ◽  
R Dyche Mullins
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Actin Filaments ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Genotoxic Stress ◽  
Nuclear Actin ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Serum Stimulation

Actin filaments assemble inside the nucleus in response to multiple cellular perturbations, including heat shock, protein misfolding, integrin engagement, and serum stimulation. We find that DNA damage also generates nuclear actin filaments—detectable by phalloidin and live-cell actin probes—with three characteristic morphologies: (i) long, nucleoplasmic filaments; (ii) short, nucleolus-associated filaments; and (iii) dense, nucleoplasmic clusters. This DNA damage-induced nuclear actin assembly requires two biologically and physically linked nucleation factors: Formin-2 and Spire-1/Spire-2. Formin-2 accumulates in the nucleus after DNA damage, and depletion of either Formin-2 or actin's nuclear import factor, importin-9, increases the number of DNA double-strand breaks (DSBs), linking nuclear actin filaments to efficient DSB clearance. Nuclear actin filaments are also required for nuclear oxidation induced by acute genotoxic stress. Our results reveal a previously unknown role for nuclear actin filaments in DNA repair and identify the molecular mechanisms creating these nuclear filaments.

scholarly journals The F-Box DNA Helicase Fbh1 Prevents Rhp51-Dependent Recombination without Mediator Proteins

2005 ◽  
Vol 25 (18) ◽  
pp. 8084-8096 ◽  
Author(s):  
Fekret Osman ◽  
Julie Dixon ◽  
Alexis R. Barr ◽  
Matthew C. Whitby
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein A ◽  
Dna Binding Protein ◽  
Inhibitory Effect ◽  
Dna Helicase ◽  
Strand Exchange ◽  
Critical Function ◽  
Single Stranded Dna ◽  
Filament Assembly

ABSTRACT A key step in homologous recombination is the loading of Rad51 onto single-stranded DNA to form a nucleoprotein filament that promotes homologous DNA pairing and strand exchange. Mediator proteins, such as Rad52 and Rad55-Rad57, are thought to aid filament assembly by overcoming an inhibitory effect of the single-stranded-DNA-binding protein replication protein A. Here we show that mediator proteins are also required to enable fission yeast Rad51 (called Rhp51) to function in the presence of the F-box DNA helicase Fbh1. In particular, we show that the critical function of Rad22 (an orthologue of Rad52) in promoting Rhp51-dependent recombination and DNA repair can be mostly circumvented by deleting fbh1. Similarly, the reduced growth/viability and DNA damage sensitivity of an fbh1 − mutant are variously suppressed by deletion of any one of the mediators Rad22, Rhp55, and Swi5. From these data we propose that Rhp51 action is controlled through an interplay between Fbh1 and the mediator proteins. Colocalization of Fbh1 with Rhp51 damage-induced foci suggests that this interplay occurs at the sites of nucleoprotein filament assembly. Furthermore, analysis of different fbh1 mutant alleles suggests that both the F-box and helicase activities of Fbh1 contribute to controlling Rhp51.

scholarly journals Actin binding to WH2 domains regulates nuclear import of the multifunctional actin regulator JMY

2012 ◽  
Vol 23 (5) ◽  
pp. 853-863 ◽  
Author(s):  
J. Bradley Zuchero ◽  
Brittany Belin ◽  
R. Dyche Mullins
Keyword(s):  
Dna Damage ◽  
Actin Filament ◽  
Nuclear Localization ◽  
Nuclear Import ◽  
Actin Polymerization ◽  
Regulatory Protein ◽  
Actin Binding ◽  
Nuclear Localization Sequence ◽  
Filament Assembly ◽  
Localization Sequence

Junction-mediating and regulatory protein (JMY) is a regulator of both transcription and actin filament assembly. In response to DNA damage, JMY accumulates in the nucleus and promotes p53-dependent apoptosis. JMY's actin-regulatory activity relies on a cluster of three actin-binding Wiskott–Aldrich syndrome protein homology 2 (WH2) domains that nucleate filaments directly and also promote nucleation activity of the Arp2/3 complex. In addition to these activities, we find that the WH2 cluster overlaps an atypical, bipartite nuclear localization sequence (NLS) and controls JMY's subcellular localization. Actin monomers bound to the WH2 domains block binding of importins to the NLS and prevent nuclear import of JMY. Mutations that impair actin binding, or cellular perturbations that induce actin filament assembly and decrease the concentration of monomeric actin in the cytoplasm, cause JMY to accumulate in the nucleus. DNA damage induces both cytoplasmic actin polymerization and nuclear import of JMY, and we find that damage-induced nuclear localization of JMY requires both the WH2/NLS region and importin β. On the basis of our results, we propose that actin assembly regulates nuclear import of JMY in response to DNA damage.

Long-term efficacy of a new medical device containing Fernblock® and DNA repair enzyme complex in the treatment and prevention of cancerization field in patients with actinic keratosis.

2019 ◽  
Vol 2 (02) ◽  
pp. 80-89
Author(s):  
Blanca De Unamuno Bustos ◽  
Natalia Chaparr´´o Aguilera ◽  
Inmaculada Azorín García ◽  
Anaid Calle Andrino ◽  
Margarita Llavador Ros ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Medical Device ◽  
Actinic Keratosis ◽  
Statistical Significance ◽  
Dna Lesions ◽  
Enzyme Complex ◽  
Repair Enzyme ◽  
P53 Expression ◽  
Cancerization Field

Actinic keratosis (AKs) are part of the cancerization field, a region adjacent to AKs containing subclinical and histologically abnormal epidermal tissue due to Ultraviolet (UV)-induced DNA damage. The photoproducts as consequence of DNA damage induced by UV are mainly cyclobutane pyrimidine dimers (CPDs). Fernblock® demonstrated in previous studies significant reduction of the number of CPDs induced by UV radiation. Photolyases are a specific group of enzymes that remove the major UV-induced DNA lesions by a mechanism called photo-reactivation. A monocentric, prospective, controlled, and double blind interventional study was performed to evaluate the effect of a new medical device (NMD) containing a DNA-repair enzyme complex (photolyases, endonucleases and glycosilases), a combination of UV-filters, and Fernblock® in the treatment of the cancerization field in 30 AK patients after photodynamic therapy. Patients were randomized into two groups: patients receiving a standard sunscreen (SS) andpatients receiving the NMD. Clinical, dermoscopic, reflectance confocal microscopy (RCM) and histological evaluations were performed. An increase of AKs was noted in all groups after three months of PDT without significant differences between them (p=0.476). A significant increase in the number of AKs was observed in SS group after six (p=0.026) and twelve months of PDT (p=0.038); however, this increase did not reach statistical significance in the NMD group. Regarding RCM evaluation, honeycomb pattern assessment after twelve months of PDT showed significant differences in the extension and grade of the atypia in the NMD group compared to SS group (p=0.030 and p=0.026, respectively). Concerning histopathological evaluation, keratinocyte atypia grade improved from baseline to six months after PDT in all the groups, with no statistically significant differences between the groups. Twelve months after PDT, p53 expression was significantly lower in the NMD group compared to SS group (p=0.028). The product was well-tolerated, with no serious adverse events reported. Our results provide evidence of the utility of this NMD in the improvement of the cancerization field and in the prevention of the development of new AKs.  

scholarly journals A Role for Histone H2B During Repair of UV-Induced DNA Damage in Saccharomyces cerevisiae

Genetics ◽  
2002 ◽  
Vol 160 (4) ◽  
pp. 1375-1387
Author(s):  
Emmanuelle M D Martini ◽  
Scott Keeney ◽  
Mary Ann Osley
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Chromatin Structure ◽  
Specific Effect ◽  
Cell Killing ◽  
Cyclobutane Pyrimidine Dimers ◽  
Histone H2b ◽  
Uv Sensitivity ◽  
Pyrimidine Dimers

Abstract To investigate the role of the nucleosome during repair of DNA damage in yeast, we screened for histone H2B mutants that were sensitive to UV irradiation. We have isolated a new mutant, htb1-3, that shows preferential sensitivity to UV-C. There is no detectable difference in bulk chromatin structure or in the number of UV-induced cis-syn cyclobutane pyrimidine dimers (CPD) between HTB1 and htb1-3 strains. These results suggest a specific effect of this histone H2B mutation in UV-induced DNA repair processes rather than a global effect on chromatin structure. We analyzed the UV sensitivity of double mutants that contained the htb1-3 mutation and mutations in genes from each of the three epistasis groups of RAD genes. The htb1-3 mutation enhanced UV-induced cell killing in rad1Δ and rad52Δ mutants but not in rad6Δ or rad18Δ mutants, which are defective in postreplicational DNA repair (PRR). When combined with other mutations that affect PRR, the histone mutation increased the UV sensitivity of strains with defects in either the error-prone (rev1Δ) or error-free (rad30Δ) branches of PRR, but did not enhance the UV sensitivity of a strain with a rad5Δ mutation. When combined with a ubc13Δ mutation, which is also epistatic with rad5Δ, the htb1-3 mutation enhanced UV-induced cell killing. These results suggest that histone H2B acts in a novel RAD5-dependent branch of PRR.

scholarly journals Environmentally Relevant Mixture of Pesticides Affect Mobility and DNA Integrity of Early Life Stages of Rainbow Trout (Oncorhynchus mykiss)

Toxics ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 174
Author(s):  
Shannon Weeks Santos ◽  
Jérôme Cachot ◽  
Bettie Cormier ◽  
Nicolas Mazzella ◽  
Pierre-Yves Gourves ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Rainbow Trout ◽  
Oncorhynchus Mykiss ◽  
Protein Carbonyl ◽  
Swimming Activity ◽  
Mitochondrial Metabolism ◽  
Pesticide Mixture ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Mixture Concentration

The aim of this study was to analyze the impact of three concentrations of a pesticide mixture on the first development stages of rainbow trout (Oncorhynchus mykiss). The mixture was made up of three commonly used pesticides in viticulture: glyphosate (GLY), chlorpyrifos (CPF) and copper sulfate (Cu). Eyed stage embryos were exposed for 3 weeks to three concentrations of the pesticide mixture. Lethal and sub-lethal effects were assessed through a number of phenotypic and molecular endpoints including survival, hatching delay, hatching success, biometry, swimming activity, DNA damage (Comet assay), lipid peroxidation (TBARS), protein carbonyl content and gene expression. Ten target genes involved in antioxidant defenses, DNA repair, mitochondrial metabolism and apoptosis were analyzed using real-time RT-qPCR. No significant increase of mortality, half-hatch, growth defects, TBARS and protein carbonyl contents were observed whatever the pesticide mixture concentration. In contrast, DNA damage and swimming activity were significantly more elevated at the highest pesticide mixture concentration. Gene transcription was up-regulated for genes involved in detoxification (gst and mt1), DNA repair (ogg1), mitochondrial metabolism (cox1 and 12S), and cholinergic system (ache). This study highlighted the induction of adaptive molecular and behavioral responses of rainbow trout larvae when exposed to environmentally realistic concentrations of a mixture of pesticides.

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