DNA repair glycosylases with a [4Fe–4S] cluster: A redox cofactor for DNA-mediated charge transport?

The [4Fe–4S] cluster is ubiquitous to a class of base excision repair enzymes in organisms ranging from bacteria to man and was first considered as a structural element, owing to its redox stability under physiological conditions. When studied bound to DNA, two of these repair proteins (MutY and Endonuclease III from Escherichia coli) display DNA-dependent reversible electron transfer with characteristics typical of high potential iron proteins. These results have inspired a reexamination of the role of the [4Fe–4S] cluster in this class of enzymes. Might the [4Fe–4S] cluster be used as a redox cofactor to search for damaged sites using DNA-mediated charge transport, a process well known to be highly sensitive to lesions and mismatched bases? Described here are experiments demonstrating the utility of DNA-mediated charge transport in characterizing these DNA-binding metalloproteins, as well as efforts to elucidate this new function for DNA as an electronic signaling medium among the proteins

Biological contexts for DNA charge transport chemistry

Many experiments have now shown that double helical DNA can serve as a conduit for efficient charge transport (CT) reactions over long distances in vitro. These results prompt the consideration of biological roles for DNA-mediated CT. DNA CT has been demonstrated to occur in biologically relevant environments such as within the mitochondria and nuclei of HeLa cells as well as in isolated nucleosomes. In mitochondria, DNA damage that results from CT is funneled to a crucial regulatory element. Thus, DNA CT provides a strategy to funnel damage to particular sites in the genome. DNA CT might also be important in long-range signaling to DNA-bound proteins. Both DNA repair proteins, containing Fe-S clusters, and the transcription factor, p53, which is regulated through thiol-disulfide switches, can be oxidized from a distance through DNA-mediated CT. These observations highlight a means through which oxidative stress may be chemically signaled in the genome over long distances through CT from guanine radicals to DNA-bound proteins. Moreover, DNA-mediated CT may also play a role in signaling among DNA-binding proteins, as has been proposed as a mechanism for how DNA repair glycosylases more efficiently detect lesions inside the cell

Direct Electrochemistry of Endonuclease III in the Presence and Absence of DNA

The electrochemistry of the base excision repair enzyme Endonuclease III (Endo III) in the presence and absence of DNA has been examined on highly oriented pyrolytic graphite (HOPG). At the surface modified with pyrenated DNA, a reversible signal is observed at 20 mV versus NHE for the [4Fe−4S]^(3+/2+) couple of Endo III, similar to Au. Without DNA modification, oxidative and reductive signals for the [4Fe−4S] cluster of Endo III are found on bare HOPG, allowing a direct comparison between DNA-bound and free redox potentials. These data indicate a shift of approximately −200 mV in the 3+/2+ couple upon binding of Endo III to DNA. This potential shift reflects a difference in affinity for DNA of more than 3 orders of magnitude between the oxidized 3+ and reduced 2+ protein and provides quantitative support for our model utilizing DNA-mediated charge transport to redistribute base excision repair enzymes in the vicinity of damaged DNA

Security in university residence halls: effects of physical design and management policies

Call number: LD2668 .T4 1978 B62Master of Architectur

Protein-DNA charge transport: Redox activation of a DNA repair protein by guanine radical

DNA charge transport (CT) chemistry provides a route to carry out oxidative DNA damage from a distance in a reaction that is sensitive to DNA mismatches and lesions. Here, DNA-mediated CT also leads to oxidation of a DNA-bound base excision repair enzyme, MutY. DNA-bound Ru(III), generated through a flash/quench technique, is found to promote oxidation of the [4Fe-4S](2+) cluster of MutY to [4Fe-4S](3+) and its decomposition product [3Fe-4S](1+). Flash/quench experiments monitored by EPR spectroscopy reveal spectra with g = 2.08, 2.06, and 2.02, characteristic of the oxidized clusters. Transient absorption spectra of poly(dGC) and [Ru(phen)(2)dppz](3+) (dppz = dipyridophenazine), generated in situ, show an absorption characteristic of the guanine radical that is depleted in the presence of MutY with formation instead of a long-lived species with an absorption at 405 nm; we attribute this absorption also to formation of the oxidized [4Fe-4S](3+) and [3Fe4S](1+) clusters. In ruthenium-tethered DNA assemblies, oxidative damage to the 5'-G of a 5'-GG-3' doublet is generated from a distance but this irreversible damage is inhibited by MutY and instead EPR experiments reveal cluster oxidation. With ruthenium-tethered assemblies containing duplex versus single-stranded regions, MutY oxidation is found to be mediated by the DNA duplex, with guanine radical as an intermediate oxidant; guanine radical formation facilitates MutY oxidation. A model is proposed for the redox activation of DNA repair proteins through DNA CT, with guanine radicals, the first product under oxidative stress, in oxidizing the DNA-bound repair proteins, providing the signal to stimulate DNA repair

Social anxiety and attentional biases: A top-down contribution?

Selective attention toward threatening facial expressions has been found to precipitate and maintain symptoms of social anxiety. However, the automaticity of this bias is under debate. In the present study, we aimed to test whether top-down (controlled) engagement and disengagement of attention toward threatening faces is associated with social anxiety. This was examined by testing the impact of a secondary working memory (WM) load on attentional biases. In a variation of the dot-probe task, participants' attention was initially cued to the left or right of fixation before an upright face paired with an inverted face was presented (displaying a disgust or neutral expression), and participants responded to a subsequently presented probe. The task was performed under no-load, low-load (one-digit memory task), and high-load (six-digit memory task) conditions. Social anxiety was not found to be associated with delayed disengagement from threat. However, surprisingly, high social anxiety was associated with an engagement bias away from threat, whereas low social anxiety was associated with a bias toward threat. These results were unaffected by the WM load manipulation. This indicates that engagement with threatening facial expressions has minimal contributions from top-down mechanisms, since it is likely that orienting to facial expressions occurs relatively automatically.This research was supported by an Australian Research Council (ARC) Discovery Early Career Research Award (DE140101734) awarded to S.C.G

Ductus arteriosus aneurysm presenting as pulmonary artery obstruction: Diagnosis and management

The occurrence of pulmonary artery obstruction in an 8 day old infant as a complication of an aneurysm of a nonpatent ductus arteriosus is reported, together with the echocardiographic and angiographic findings. To relieve the obstruction, the aneurysm and an intrapulmonary thrombus were successfully removed with the use of cardiopulmonary bypass when the infant was 3 months old

An Improved Quantum Molecular Dynamics Model and its Applications to Fusion Reaction near Barrier

An improved Quantum Molecular Dynamics model is proposed. By using this model, the properties of ground state of nuclei from $^{6}$Li to $^{208}$Pb can be described very well with one set of parameters. The fusion reactions for $^{40}$Ca+$^{90}$Zr, $^{40}$Ca+$^{96}$Zr and $^{48}$Ca+$^{90}$Zr at energy near barrier are studied by this model. The experimental data of the fusion cross sections for $^{40}$Ca+$^{90,96}$Zr at the energy near barrier can be reproduced remarkably well without introducing any new parameters. The mechanism for the enhancement of fusion probability for fusion reactions with neutron-rich projectile or target is analyzed.Comment: 20 pages, 12 figures, 3 table

Force steps during viral DNA packaging ?

Biophysicists and structural biologists increasingly acknowledge the role played by the mechanical properties of macromolecules as a critical element in many biological processes. This change has been brought about, in part, by the advent of single molecule biophysics techniques that have made it possible to exert piconewton forces on key macromolecules and observe their deformations at nanometer length scales, as well as to observe the mechanical action of macromolecules such as molecular motors. This has opened up immense possibilities for a new generation of mechanical investigations that will respond to such measurements in an attempt to develop a coherent theory for the mechanical behavior of macromolecules under conditions where thermal and chemical effects are on an equal footing with deterministic forces. This paper presents an application of the principles of mechanics to the problem of DNA packaging, one of the key events in the life cycle of bacterial viruses with special reference to the nature of the internal forces that are built up during the DNA packaging process.Comment: 18 pages, 7 figures, To appear in the Journal of Mechanics and Physics of Solid

Dynamic study on fusion reactions for 40,48^{40,48}Ca+90,96^{90,96}Zr around Coulomb barrier

By using the updated improved Quantum Molecular Dynamics model in which a surface-symmetry potential term has been introduced for the first time, the excitation functions for fusion reactions of $^{40,48}$Ca+$^{90,96}$Zr at energies around the Coulomb barrier have been studied. The experimental data of the fusion cross sections for $^{40}$Ca+$^{90,96}$Zr have been reproduced remarkably well without introducing any new parameters. The fusion cross sections for the neutron-rich fusion reactions of $^{48}$Ca+$^{90,96}$Zr around the Coulomb barrier are predicted to be enhanced compared with a non-neutron-rich fusion reaction. In order to clarify the mechanism of the enhancement of the fusion cross sections for neutron-rich nuclear fusions, we pay a great attention to study the dynamic lowering of the Coulomb barrier during a neck formation. The isospin effect on the barrier lowering is investigated. It is interesting that the effect of the projectile and target nuclear structure on fusion dynamics can be revealed to a certain extent in our approach. The time evolution of the N/Z ratio at the neck region has been firstly illustrated. A large enhancement of the N/Z ratio at neck region for neutron-rich nuclear fusion reactions is found.Comment: 21 pages, 7 figures,3 table