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PubMed2005

Involvement of vertebrate Polkappa in translesion DNA synthesis across DNA monoalkylation damage.

DNA lesions that escape excision repair pathways can cause arrested DNA replication. This replication block can be processed by translesion DNA synthesis (TLS), which is carried out by a number of specialized DNA polymerases. A sequential lesion bypass model has been proposed; one of the lesion-specific polymerases inserts nucleotide(s) opposite the damaged template, followed by extension from the inserted nucleotide by the same or another polymerase. Polzeta and Polkappa have been proposed as candidates for executing the extension step in eukaryotic cells. We previously disrupted separately Rev3, the catalytic subunit of Polzeta, and Polkappa in chicken B lymphocyte DT40 cells. We found that each cell line showed significant UV sensitivity, implying that both contribute to UV radiation damage repair. In the present studies we generated REV3(-/-)POLK(/-) double knock-out cells to determine whether they participate in the same or different pathways. The double mutant was viable and proliferated with the same kinetics as parental REV3(-/-) cells. The cells showed the same sensitivity as REV3(-/-) cells to UV, ionizing radiation, and chemical cross-linking agents. In contrast, they were more sensitive than REV3(-/-) cells to monofunctional alkylating agents, even though POLK(/-) cells barely exhibited increased sensitivity to those. Moreover Polk-deficient mouse embryonic stem and fibroblast cells, both of which have previously been shown to be sensitive to UV radiation, also showed moderate sensitivity to methyl methanesulfonate, a monofunctional alkylating agent. These data imply that Polkappa has a function in TLS past alkylated base adducts as well as UV radiation DNA damage in vertebrates.

Alkylating Agents↗

PubMed2004

Improving promoter prediction for the NNPP2.2 algorithm: a case study using Escherichia coli DNA sequences.

MOTIVATION: Although a great deal of research has been undertaken in the area of promoter prediction, prediction techniques are still not fully developed. Many algorithms tend to exhibit poor specificity, generating many false positives, or poor sensitivity. The neural network prediction program NNPP2.2 is one such example. RESULTS: To improve the NNPP2.2 prediction technique, the distance between the transcription start site (TSS) associated with the promoter and the translation start site (TLS) of the subsequent gene coding region has been studied for Escherichia coli K12 bacteria. An empirical probability distribution that is consistent for all E.coli promoters has been established. This information is combined with the results from NNPP2.2 to create a new technique called TLS-NNPP, which improves the specificity of promoter prediction. The technique is shown to be effective using E.coli DNA sequences, however, it is applicable to any organism for which a set of promoters has been experimentally defined. AVAILABILITY: The data used in this project and the prediction results for the tested sequences can be obtained from http://www.uow.edu.au/~yanxia/E_Coli_paper/SBurden_Results.xls CONTACT: alh98@uow.edu.au.

Algorithms↗

PubMed2000

Repair of chromosomal abasic sites in vivo involves at least three different repair pathways.

We introduced multiple abasic sites (AP sites) in the chromosome of repair-deficient mutants of Escherichia coli, in vivo, by expressing engineered variants of uracil-DNA glycosylase that remove either thymine or cytosine. After introduction of AP sites, deficiencies in base excision repair (BER) or recombination were associated with strongly enhanced cytotoxicity and elevated mutation frequencies, selected as base substitutions giving rifampicin resistance. In these strains, increased fractions of transversions and untargeted mutations were observed. In a recA mutant, deficient in both recombination and translesion DNA synthesis (TLS), multiple AP sites resulted in rapid cell death. Preferential incorporation of dAMP opposite a chromosomal AP site ('A rule') required UmuC. Furthermore, we observed an 'A rule-like' pattern of spontaneous mutations that was also UmuC dependent. The mutation patterns indicate that UmuC is involved in untargeted mutations as well. In a UmuC-deficient background, a preference for dGMP was observed. Spontaneous mutation spectra were generally strongly dependent upon the repair background. In conclusion, BER, recombination and TLS all contribute to the handling of chromosomal AP sites in E.coli in vivo.

Amino Acid Substitution↗

PubMed2006

A case of metastatic testicular cancer complicated by tumour lysis syndrome and choriocarcinoma syndrome.

A 26-year-old man was referred to our hospital for treatment of metastatic testicular cancer. The pathological diagnosis was choriocarcinoma with seminoma. Sequential computerized tomography examinations revealed rapidly progressing bulky liver metastases and a lung metastasis. Chemotherapy with bleomycin, etoposide and cisplatin (BEP) was started on the day of admission. Subsequently, the patient suffered from tumour lysis syndrome (TLS) and massive haemorrhage at metastatic sites. The latter complication is also called choriocarcinoma syndrome. To our knowledge, this is the first case report of testicular cancer complicated with both critical conditions. Intensive care and radiological intervention barely prevented a fatal outcome. The urological oncologist should be aware of the potential complications TLS and choriocarcinoma syndrome in cases of rapidly progressive and high-volume choriocarcinoma.

Adult↗

PubMed2003

Mitochondria-mediated nuclear mutator phenotype in Saccharomyces cerevisiae.

Using Saccharomyces cerevisiae as a model organism, we analyzed the consequences of disrupting mitochondrial function on mutagenesis of the nuclear genome. We measured the frequency of canavanine-resistant colonies as a measure of nuclear mutator phenotype. Our data suggest that mitochondrial dysfunction leads to a nuclear mutator phenotype (i) when oxidative phosphorylation is blocked in wild-type yeast at mitochondrial complex III by antimycin A and (ii) in mutant strains lacking the entire mitochondrial genome (rho(0)) or those with deleted mitochondrial DNA (rho(-)). The nuclear mutation frequencies obtained for antimycin A-treated cells as well as for rho(-) and rho(0) cells were approximately 2- to 3-fold higher compared to untreated control and wild-type cells, respectively. Blockage of oxidative phosphorylation by antimycin A treatment led to increased intracellular levels of reactive oxygen species (ROS). In contrast, inactivation of mitochondrial activity (rho(-) and rho(0)) led to decreased intracellular levels of ROS. We also demonstrate that in rho(0) cells the REV1, REV3 and REV7 gene products, all implicated in error-prone translesion DNA synthesis (TLS), mediate mutagenesis in the nuclear genome. However, TLS was not involved in nuclear DNA mutagenesis caused by inhibition of mitochondrial function by antimycin A. Together, our data suggest that mitochondrial dysfunction is mutagenic and multiple pathways are involved in this nuclear mutator phenotype.

Antimycin A↗

PubMed1994

The M1 antagonist pirenzepine suppresses heterosynaptic STD in the CA1 region.

The effect of the muscarinic M1 and M2 antagonists (pirenzepine and gallamine) on heterosynaptic short-term depression (HSTD) of the CA1 population spike was studied in rat hippocampal slices. HSTD was evoked by a train of 30-50 pulses at 5 Hz (theta-like stimulation; TLS) delivered to the stratum oriens. Bath-applied pirenzepine (10(-6)-3 x 10(-6) M) significantly suppressed the magnitude of HSTD in the tested radiatum input (56 +/- 26% of control, p < 0.05). In contrast, gallamine (10(-6)-10(-5) M) did not suppress HSTD (102 +/- 7%). An enhancement of HSTD during application of eserine was also antagonized by pirenzepine (71 +/- 18%, p < 0.01), but not by gallamine (152 +/- 85%). These data suggest that acetylcholine synaptically released during TLS of the stratum oriens significantly contributes to HSTD in the CA1 region by activation of the M1 muscarinic receptor subtype.

Acetylcholine↗

PubMed1996

Tumor lysis syndrome: implications for nursing.

Tumor Lysis Syndrome (TLS) is a potential consequence of antineoplastic therapy, causing metabolic disturbances that if left untreated, may result in potentially fatal renal, cardiac, and neurologic complications. Early identification and prompt interventions are necessary to treat the metabolic disturbances of TLS. As more therapies are directed toward ambulatory care and home care settings, identification of patients at risk for potential complications associated with antineoplastic administration is more crucial than ever.

Home Care Services↗

PubMed1997

White matter neuronal heterotopia in temporal lobe epilepsy: a morphometric and immunohistochemical study.

A frequent abnormality in temporal lobes (TL) resected for pharmacoresistant epilepsy is the presence of heterotopic neurons within white matter (WM). We compared heterotopic neuron density in 22 TLs surgically resected from epilepsy patients with TLs from 22 non-neurologic cases obtained at autopsies. Neuronal density was assessed on LFB-PAS-stained and parallel sections immunoreacted for microtubule-associated-protein-2 (MAP-2). The white matter area was outlined by an image analysis system. Neurons, identified by morphologic features, were counted within the marked area. Results are expressed as mean +/- SD neurons/mm2. LFB/PAS sections: Epilepsy cases 4.11 +/- 1.86 Autopsy (normal) 2.35 +/- 0.96; MAP-2 sections: Epilepsy cases 4.08 +/- 1.22, autopsy (normal) 1.68 +/-0.92 (significant at 0.05 level by Wilcoxon's Rank Sums test). The lower number of MAP-2-immunopositive neurons in the control group as compared with the histologically identified group is most likely the result of antigen degradation resulting from an increased postmortem interval. These results indicate that normal TLWM contains a heterotopic population of neurons, and that this neuronal density is significantly higher in epilepsy patients. It is felt that this increased neuronal density is an epiphenomenon rather than the cause of seizures, and may be the result of decreased white matter either secondary to disruption of myelination, or loss of neurons as part of mesial temporal sclerosis.

Adolescent↗

PubMed2001

Tumor lysis syndrome in an infant with Langerhans cell histiocytosis successfully treated using continuous arteriovenous hemofiltration.

Langerhans cell histiocytosis (LCH) is an enigmatic disease usually occurring in children. Tumor lysis syndrome (TLS) is a clinical syndrome associated with severe metabolic derangement and oliguric acute renal failure. In this report, we present the clinical course of an infant with advanced LCH who had TLS develop after chemotherapy. Treatment with continuous arteriovenous hemofiltration resulted in effective control of serum uric acid, potassium, creatinine, phosphorus, and blood urea nitrogen levels in the blood.

Acute Kidney Injury↗

PubMed2004

Early and mid-term results of totally laparoscopic surgery for aortoiliac disease: lessons learned.

The present article is the first in the literature reporting short- and medium-term results using a totally laparoscopic technique for aortoiliac disease.Forty-nine patients, 6 having an associated small aneurysm, were scheduled for totally laparoscopic surgery (TLS) for aortoiliac occlusive disease and 2 for treatment of aortic aneurysmal disease (AAA). Patients' characteristics, intraoperative, postoperative data and mid-term data were recorded.TLS was successfully completed in 45 patients. Of those patients, 41 received an aortobifemoral bypass; three, an iliofemoral bypass; and one, an aortoaortic bypass. Five patients were converted from TLS to video-assisted laparoscopic surgery using incisions varying in size from 7 cm to 11 cm. One patient underwent conversion to standard open surgery. One death occurred unrelated to the technique. Major perioperative complications related to the technique were few and presented in the early phase of the study: One intraoperative embolization to the lower limbs that needed embolectomy, and one acute aortic false aneurysm. Midterm results were favorable, demonstrating two limb graft thromboses. Hernias at trocar sites occurred in only 3.9%. The patients benefited from this procedure, which is considered definitive like its standard open counterpart. The conversion rate is lower than that reported for acute cholecystitis. Selection of patients has been less stringent during the second half of the study in term of inclusion of patients with AAA and of more TASC IV patients. Surgeons willing to learn this technique should attend dedicated courses. In the future, as this surgical innovation matures, controlled randomized studies should be initiated.

Adult↗

PubMed2001

DNA polymerase iota and related rad30-like enzymes.

Until recently, the molecular mechanisms of translesion DNA synthesis (TLS), a process whereby a damaged base is used as a template for continued replication, was poorly understood. This area of scientific research has, however, been revolutionized by the finding that proteins long implicated in TLS are, in fact, DNA polymerases. Members of this so-called UmuC/DinB/Rev1/Rad30 superfamily of polymerases have been identified in prokaryotes, eukaryotes and archaea. Biochemical studies with the highly purified polymerases reveal that some, but not all, can traverse blocking lesions in template DNA. All of them share a common feature, however, in that they exhibit low fidelity when replicating undamaged DNA. Of particular interest to us is the Rad30 subfamily of polymerases found exclusively in eukaryotes. Humans possess two Rad30 paralogs, Rad30A and Rad30B. The RAD30A gene encodes DNA polymerase eta and defects in the protein lead to the xeroderma pigmentosum variant (XP-V) phenotype in humans. Very recently RAD30B has also been shown to encode a novel DNA polymerase, designated as Pol iota. Based upon in vitro studies, it appears that Pol iota has the lowest fidelity of any eukaryotic polymerase studied to date and we speculate as to the possible cellular functions of such a remarkably error-prone DNA polymerase.

Bacterial Proteins↗

PubMed1999

Quantum stochastic resonance in symmetric systems.

We investigate the low-temperature quantum stochastic resonance (QSR) phenomenon in a two-level system (TLS) which is coupled to an Ohmic heat bath. In contrast to common belief we find that QSR occurs also for symmetric (i.e., unbiased) TLS's if the viscous friction parameter alpha exceeds a critical value: We demonstrate that with respect to the spectral power amplification measure QSR always occurs for alpha>1; in contrast, the output signal-to-noise ratio exhibits an amplification only for alpha>3/2.

Journal Article↗

PubMed2000

Distributions and size scalings for strength in a one-dimensional random lattice with load redistribution to nearest and next-nearest neighbors

Lattice and network models with elements that have random strength are useful tools in explaining various statistical features of failure in heterogeneous materials, including the evolution of failure clusters and overall strength distributions and size effects. Models have included random fuse and spring networks where Monte Carlo simulation coupled to scaling analysis from percolation theory has been a common approach. Unfortunately, severe computational demands have limited the network sizes that can be treated. To gain insight at large size scales, interest has returned to idealized fiber bundle models in one dimension. Many models can be solved exactly or asymptotically in increasing size n, but at the expense of major simplification of the local stress redistribution mechanism. Models have typically assumed either equal load-sharing among nonfailed elements, or nearest-neighbor, local load-sharing (LLS) where a failed element redistributes its load onto its two nearest flanking survivors. The present work considers a one-dimensional fiber bundle model under tapered load sharing (TLS), which assumes load redistribution to both the nearest and next-nearest neighbors in a two-to-one ratio. This rule reflects features found in a discrete mechanics model for load transfer in two-dimensional fiber composites and planar lattices. We assume that elements have strength 1 or 0, with probability p and q=1-p, respectively. We determine the structure and probabilities for critical configurations of broken fibers, which lead to bundle failure under a given load. We obtain rigorous asymptotic results for the strength distribution and size effect, as n-->infinity, with precisely determined constants and exponents. The results are a nontrivial extension of those under LLS in that failure clusters are combinatorially much more complicated and contain many bridging fibers. Consequently, certain probabilities are eigenvalues from recursive equations arising from the structure of TLS. Next-nearest neighbor effects weaken the material beyond what is predicted under LLS keeping only nearest neighbor overloads. Our results question the validity of scaling relationships that are based largely on Monte Carlo simulations on networks of limited size since some failure configurations appear only in extremely large bundles. The dilemma has much in common with the Petersburg paradox.

Journal Article↗

PubMed2003

A neutron diffraction study of xylitol: derivation of mean square internal vibrations for H atoms from a rigid-body description.

A neutron diffraction study of xylitol (C(5)O(5)H(12)) is presented. The nuclear anisotropic displacement parameters have been analysed showing that the carbon-oxygen skeleton conforms to a rigid-body (TLS) description. Applying this TLS model to the xylitol H atoms allows characterization of the internal molecular displacements of the H nuclei, assuming that the observed H nuclear mean-square displacements are a sum of the internal displacements and rigid-body displacements. These internal molecular displacements are very similar for chemically equivalent H atoms and in good agreement with the values obtained by other methods. In all cases the smallest eigenvector of the residual mean-square displacement tensor is almost parallel to the X-H bond. The use of ab initio calculations to obtain the internal vibrations in xylitol is discouraging. Another 12 structures extracted from the literature which have been investigated by neutron diffraction were subjected to a similar analysis. The results for the nine compounds investigated at low temperature conform to the results from xylitol and provide estimates of the internal vibrations of H atoms in a range of chemical environments.

Journal Article↗

PubMed2004

Strategies for the structure determination of endohedral fullerenes applied to the example of Ba@C(74)xCo(octaethylporphyrin)x2C(6)H(6).

The structure determination of endohedral fullerenes is complicated because of the high degree of disorder which may affect the different structural components, e.g. the endohedral atom/molecule, the fullerene cage and solvent molecules. Even worse, the data-to-parameter ratio and, in particular, the scattering power is low. Different strategies are employed to deal with these problems. The observed fraction of the reciprocal lattice may be increased by means of synchrotron diffraction studies. The number of parameters may be reduced by applying rigid-body refinement strategies and by restricting the displacement parameters in the framework of the TLS approach. In the first section, we will give a short overview of the structure determinations of endohedral fullerenes from single-crystal data and discuss the severe problems one may encounter. Then we will give an example of a successful structure analysis of a metal-containing endohedral fullerene, i.e. Ba@C(74)xCo(OEP)x2C(6)H(6) (OEP = octaethylporphyrin). Several strategies of refinement, beyond the black box level, have been checked and compared, e.g. TLS, split-atom models, twin and single crystal models, anharmonic displacement parameters, and rigid-body models.

Journal Article↗

PubMed2003

Domain flexibility in the 1.75 A resolution structure of Pb2+-calmodulin.

Calmodulin (CaM) regulates a variety of cellular processes by interacting with a large number of proteins in a Ca(2+)-dependent manner. Conformational flexibility plays a key role in CaM function, although the full extent and detailed features of this flexibility are not fully characterized. Here, the 1.75 A resolution crystal structure of Pb(2+)-bound Paramecium tetraurelia CaM crystallized in a previously unobserved monoclinic lattice is reported. Pb(2+)-CaM is disordered in this new lattice and only a portion of each of the two molecules in the asymmetric unit can be modeled. Comparison of the structures of Ca(2+)-CaM and Pb(2+)-CaM show close agreement in the C-terminal domain but significant structural differences in the N-terminal domain. In addition, translation-libration-screw (TLS) refinement and Rosenfield difference analysis reveal inter-helical flexibility in the metal-bound N-terminal domain of the protein that is absent in the metal-bound C-terminal domain and indicates that the two structurally similar domains of CaM are dynamically distinct. These results demonstrate that TLS refinement and Rosenfield difference analysis allow detailed information about macromolecular flexibility to be extracted from X-ray diffraction data even when the crystal lattice prohibits full manifestation of this flexibility.

Animals↗

PubMed2005

Conformational flexibility of Mycobacterium tuberculosis thioredoxin reductase: crystal structure and normal-mode analysis.

The thioredoxin system exists ubiquitously and participates in essential antioxidant and redox-regulation processes via a pair of conserved cysteine residues. In Mycobacterium tuberculosis, which lacks a genuine glutathione system, the thioredoxin system provides reducing equivalents inside the cell. The three-dimensional structure of thioredoxin reductase from M. tuberculosis has been determined at 3 A resolution. TLS refinement reveals a large libration axis, showing that NADPH-binding domain has large anisotropic disorder. The relative rotation of the NADPH domain with respect to the FAD domain is necessary for the thioredoxin reduction cycle, as it brings the spatially distant reacting sites close together. Normal-mode analysis carried out based on the elastic network model shows that the motion required to bring about the functional conformational change can be accounted for by motion along one single mode. TLS refinement and normal-mode analysis thus enhance our understanding of the associated conformational changes.

Binding Sites↗

PubMed1995

Full-matrix refinement of the protein crambin at 0.83 A and 130 K.

This paper describes the first successful full-matrix least-squares (FMLS) refinement of a protein structure. The example used is crambin which is a small hydrophobic protein (4.7 kDa, 46 residues). It proves the feasibility of refining such large molecules by this classic method, routinely applied to small molecules. The final structure with 381 non-H protein atoms (54 protein atoms in alternative positions), 367 H atoms, 162 water molecules (combined occupancy 93) and one disordered ethanol molecule converged to a standard unweighted crystallographic R-factor of R = 9.0% when refined against F with reflections stronger than F > 2sigma(F) and R = 9.5% when refined against F(2). The programs RFINE [Finger & Prince (1975). Natl Bur. Stand. (US) Tech. Note 854. A System of Fortran IV Computer Programs for Crystal Structure Computations] and SHELXL93 [Sheldrick (1993). SHELXL93. Program for Crystal Structure Refinement, Univ. of Göttingen, Germany] were used for FMLS refinement with the high-resolution low-temperature (0.83 A, 130 K) data set of a mixed-sequence form of crambin. A detailed analysis of the models obtained in FMLS and PROLSQ [restrained least squares or RLS; Teeter, Roe & Heo (1993). J. Mol. Biol. 230, 292-311] refinements with the same data set is presented. The differences between the models obtained by both FMLS and RLS refinements are systematic but negligible and advantages and shortcomings of both methods are discussed. The final structure has very good geometry, fully comparable to the geometry of other structures in this resolution range. Ideal values used in PROLSQ and those by Engh & Huber [Engh & Huber (1991). Acta Cryst. A47, 392-400] differ significantly from this refinement and we recommend a new standard. FMLS refinement constitutes a sensitive tool to detect and model disorder in highly refined protein structures. We describe the modeling of temperature factors by the TLS method [Schomaker & Trueblood (1968). Acta Cryst. B24, 63-76]. Rigid body-TLS refinements led to a better understanding of different modes of vibrations of the molecule. Refinements using F(2) or F protocols converged and reached slightly different minima. Despite theoretical support for F(2)-based refinement, we recommend refinement on structure factors.

Journal Article↗