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PubMed2000

A two-stage discrimination of cardiac arrhythmias using a total least squares-based prony modeling algorithm.

In this paper, we describe a new approach for the discrimination among ventricular fibrillation (VF), ventricular tachycardia (VT) and superventricular tachycardia (SVT) developed using a total least squares (TLS)-based Prony modeling algorithm. Two features, dubbed energy fractional factor (EFF) and predominant frequency (PF), are both derived from the TLS-based Prony model. In general, EFF is adopted for discriminating SVT from ventricular tachyarrhythmias (i.e., VF and VT) first, and PF is then used for further separation of VF and VT. Overall classification is achieved by performing a two-stage process to the indicators defined by EFF and PF values, respectively. Tests conducted using 91 episodes drawn from the MIT-BIH database produced optimal predictive accuracy of (SVT, VF, VT) = (95.24%, 96.00%, 97.78%). A data decimation process is also introduced in the novel method to enhance the computational efficiency, resulting in a significant reduction in the time required for generating the feature values.

Algorithms↗

PubMed2005

Antiepileptic drug withdrawal after successful surgery for intractable temporal lobe epilepsy.

PURPOSE: To investigate the prognosis related to antiepileptic drug (AED) discontinuation after successful surgery for intractable temporal lobe epilepsy. METHODS: The clinical courses after temporal lobectomies (TLs) were retrospectively analyzed in 88 consecutive patients. All the patients had TLs as the only surgical procedure, and they had been followed up for longer than 3 years. AED discontinuation was attempted if the patient had been seizure free without aura for >or=1 year during the follow-up period. RESULTS: Sixty-six (75%) patients achieved complete seizure freedom for >or=1 year; 28 patients were seizure free immediately after surgery (immediate success); and 38 patients became seizure free after some period of recurrent seizures (delayed success). AED discontinuation was attempted in 60 (91%) of 66 patients with a successful outcome. In 13 (22%) patients, seizure relapse developed during AED reduction (n=60), and in seven (12%) patients after discontinuation of AEDs (n=38). The seizure recurrence rate was not different between the immediate-and delayed-success groups. Among 20 patients with seizure relapse related to AED tapering, nine (45%) of them regained seizure freedom after reinstitution of AED treatment, and AEDs were eventually discontinued in six of them. Seizures that recurred after complete AED discontinuation had a better prognosis than did the seizures that recurred during AED reduction (seizure freedom in 86% vs. 23%). At the final assessment, 54 (61%) patients had been seizure free >or=1 year; 37 without AEDs and 17 with AEDs. The successful discontinuation of AEDs was more frequent for patients with a younger age at the time of surgery and for those patients with shorter disease duration. CONCLUSIONS: Our results suggest that seizure freedom without aura at >or=1 year is a reasonable indication for the attempt at AED discontinuation. The subsequent control of recurrent seizures was excellent, especially if seizures relapsed after the complete discontinuation of AEDs. Younger age at the time of surgery and a shorter disease duration seem to affect successful AED discontinuation for a long-term period.

Adolescent↗

PubMed1991

Action site of the gene determining susceptibility to propylnitrosourea-induced thymic lymphomas in F344 rats.

To clarify whether the determining effect of the thymic lymphoma susceptible-1 (Tls-1) gene is on putative N-propyl-N-nitrosourea (PNU) target cells among T-lineage cells or on other host factors, we investigated the PNU-induced lymphomagenesis in transplantation chimeras between susceptible F344 and resistant LES strain rats. Administration of PNU to lethally irradiated (F344 x LES)F1 rats reconstituted with bone marrow cells from either F344 or LES parental rats invariably led to development of donor-origin thymic lymphomas. On the other hand, thymic lymphomas were induced in thymectomized F1 rats grafted with neonatal LES thymus, of which 4 out of 8 were of the donor origin. These observations indicate that the target cells of thymic lymphomagenesis of F344 and LES rats were equally susceptible to PNU provided they are in susceptible hosts and the LES thymus seems capable of supporting thymic lymphomagenesis, although this capability wanes with aging of the thymus. The effect of the Tls-1 gene, therefore, is neither on PNU susceptibility of the target cells nor on the capability of the thymus to support lymphomagenesis, but on other host factors either in or out of the thymus.

Animals↗

PubMed2004

Interaction of hREV1 with three human Y-family DNA polymerases.

Polkappa is one of many DNA polymerases involved in translesion DNA synthesis (TLS). It belongs to the Y-family of polymerases along with Poleta, Poliota and hREV1. Unlike Poleta encoded by the xeroderma pigmentosum variant (XPV) gene, Polkappa is unable to bypass UV-induced DNA damage in vitro, but it is able to bypass benzo[a]pyrene (B[a]P)-adducted guanines accurately and efficiently. In an attempt to identify factor(s) targeting Polkappa to its cognate DNA lesion(s), we searched for Polkappa-interacting proteins by using the yeast two-hybrid assay. We found that Polkappa interacts with a C-terminal region of hREV1. Poleta and Poliota were also found to interact with the same region of hREV1. The interaction between Polkappa and hREV1 was confirmed by pull-down and co-immunoprecipitation assays. The C-terminal region of hREV1 is known to interact with hREV7, a non-catalytic subunit of Polzeta that is another structurally unrelated TLS enzyme, and we show that Polkappa and hREV7 bind to the same C-terminal region of hREV1. Thus, our results suggest that hREV1 plays a pivotal role in the multi-enzyme, multi-step process of translesion DNA synthesis.

Amino Acid Sequence↗

PubMed1979

Temporary threshold shift, loudness, and auditory evoked potentials.

TTS2 of 20dB was produced in a group of subjects using a 1000 Hz pure tone. All TTS and related measurements were made at 1500 Hz. The recovery of TTS, and of TLS or 'temporary loudness shift' (measured against a reference tone at 20db, 40dB and 60dB SL in the opposite ear), as well as N1-P2 amplitude of the Vertex potential, were plotted. There was an orderly recovery of both TLS and TTS although the rate of recovery of the latter was noticeably more rapid. Recovery of N1-P2 amplitude was much less orderly, although it did recover in much the same way. When the amplitudes were measured at 40dB SL the recovery was more orderly and followed the course of TTS more closely. It was concluded that any relation between N1-P2 amplitude and growth of loudness was indirect.

Acoustic Stimulation↗

PubMed2006

A human DNA polymerase eta complex containing Rad18, Rad6 and Rev1; proteomic analysis and targeting of the complex to the chromatin-bound fraction of cells undergoing replication fork arrest.

DNA polymerase eta (Poleta) is responsible for efficient translesion synthesis (TLS) past cis-syn cyclobutane thymine dimers (TT dimers), the major DNA lesions induced by UV irradiation. Loss of human Poleta leads to xeroderma pigmentosum variant syndrome, clearly indicating that Poleta plays a vital role in preventing skin cancer caused by exposure to sunlight. To further examine Poleta functions and the mechanisms that regulate this important protein, Poleta complexes were purified from HeLa cells over-expressing epitope-tagged Poleta, and polypeptides associated with Poleta, including Rad18, Rad6 and Rev1, were identified by a combination of mass spectrometry and Western blot analysis. The chromatin-bound fractions of cells subjected to UV irradiation, S phase synchronization, or S phase arrest were specifically enriched in such complexes. These results suggest that arrested replication forks strengthen interactions among Poleta, Rad18/Rad6 and Rev1, consistent with the requirement for effective TLS by Poleta at sites of DNA lesions.

Chromatin↗

PubMed2005

Tumor lysis syndrome in a patient with metastatic, androgen independent prostate cancer.

Tumor lysis syndrome (TLS) is an uncommon, but well described, clinical entity that typically occurs following chemotherapy in patients with rapidly growing hematological malignancies. It is rarely described in patients with solid tumors. We report a case of TLS in a patient with metastatic adenocarcinoma of the prostate after treatment with paclitaxel chemotherapy.

Adenocarcinoma↗

PubMed2004

Genetic structure and variation in the relict populations of Alsophila spinulosa from southern China based on RAPD markers and cpDNA atpB-rbcL sequence data.

RAPD markers and sequences of chloroplast DNA (cpDNA) atpB-rbcL intergenic spacers were used to characterize the pattern of genetic variation and the phylogenetic relationships of the relict populations of Alsophila spinulosa located in Jian Feng Ling (JFL) and Diao Luo Shan (DLS), Hainan, and Tang Lang Shan (TLS), Ding Hu Shan (DHS), and Da Xi Shan (DXS), Guangdong, of southern China. 28 random primers generated 118 bands, out of which 26 (22.03%) were polymorphic loci, distinguishing 17 different RAPD phenotypes. Percentage of polymorphic loci, Shannon phenotypic diversity and Nei's gene diversity comprehensively indicated that JFL possessed the highest diversity, TLS and DHS in intermediate and DLS or DXS the least; the corresponding values of the population appeared correlated with the population size. Differentiation was detected among populations of A. spinulosa (1-Hpop/Hsp=0.7453, GST=0.7763, and phist=0.8145). AMOVA showed that 47.44% of the variance was partitioned among regions (Hainan and Guangdong), 34.01% attributed among populations within regions, whereas only 18.55% occurring within populations. Low level of intra-specific diversity was maintained in A. spinulosa with Shannon diversity and gene diversity merely 0.0560 and 0.0590, repectively. Sequence length of atpB-rbcL intergenic spacer varied from 724 bp to 730 bp. Base composition was with A+T content between 63.17% and 63.70%. 13 haplotypes of atpB-rbcL noncoding spacers were identified. UPGMA dendrogram of RAPD phenotypes, principal components analysis based on RAPD patterns, minimum spanning network and neighbour-joining (NJ) tree established on atpB-rbcL haplotypes consistently suggested the geographical subdivision of populations of A. spinulosa between Hainan and Guangdong. Breeding system and conservation strategy of A. spinulosa was discussed based on the information of population genetic structure and variation.

Base Composition↗

PubMed2001

Genetic interactions between the Escherichia coli umuDC gene products and the beta processivity clamp of the replicative DNA polymerase.

The Escherichia coli umuDC gene products encode DNA polymerase V, which participates in both translesion DNA synthesis (TLS) and a DNA damage checkpoint control. These two temporally distinct roles of the umuDC gene products are regulated by RecA-single-stranded DNA-facilitated self-cleavage of UmuD (which participates in the checkpoint control) to yield UmuD' (which enables TLS). In addition, even modest overexpression of the umuDC gene products leads to a cold-sensitive growth phenotype, apparently due to the inappropriate expression of the DNA damage checkpoint control activity of UmuD(2)C. We have previously reported that overexpression of the epsilon proofreading subunit of DNA polymerase III suppresses umuDC-mediated cold sensitivity, suggesting that interaction of epsilon with UmuD(2)C is important for the DNA damage checkpoint control function of the umuDC gene products. Here, we report that overexpression of the beta processivity clamp of the E. coli replicative DNA polymerase (encoded by the dnaN gene) not only exacerbates the cold sensitivity conferred by elevated levels of the umuDC gene products but, in addition, confers a severe cold-sensitive phenotype upon a strain expressing moderately elevated levels of the umuD'C gene products. Such a strain is not otherwise normally cold sensitive. To identify mutant beta proteins possibly deficient for physical interactions with the umuDC gene products, we selected for novel dnaN alleles unable to confer a cold-sensitive growth phenotype upon a umuD'C-overexpressing strain. In all, we identified 75 dnaN alleles, 62 of which either reduced the expression of beta or prematurely truncated its synthesis, while the remaining alleles defined eight unique missense mutations of dnaN. Each of the dnaN missense mutations retained at least a partial ability to function in chromosomal DNA replication in vivo. In addition, these eight dnaN alleles were also unable to exacerbate the cold sensitivity conferred by modestly elevated levels of the umuDC gene products, suggesting that the interactions between UmuD' and beta are a subset of those between UmuD and beta. Taken together, these findings suggest that interaction of beta with UmuD(2)C is important for the DNA damage checkpoint function of the umuDC gene products. Four possible models for how interactions of UmuD(2)C with the epsilon and the beta subunits of DNA polymerase III might help to regulate DNA replication in response to DNA damage are discussed.

Alleles↗

PubMed2002

Eukaryotic elongation factor 1A interacts with the upstream pseudoknot domain in the 3' untranslated region of tobacco mosaic virus RNA.

The genomic RNA of tobacco mosaic virus (TMV), like that of other positive-strand RNA viruses, acts as a template for both translation and replication. The highly structured 3' untranslated region (UTR) of TMV RNAs plays an important role in both processes; it is not polyadenylated but ends with a tRNA-like structure (TLS) preceded by a conserved upstream pseudoknot domain (UPD). The TLS of tobamoviral RNAs can be specifically aminoacylated and, in this state, can interact with eukaryotic elongation factor 1A (eEF1A)/GTP with high affinity. Using a UV cross-linking assay, we detected another specific binding site for eEF1A/GTP, within the UPDs of TMV and crucifer-infecting tobamovirus (crTMV), that does not require aminoacylation. A mutational analysis revealed that UPD pseudoknot conformation and some conserved primary sequence elements are required for this interaction. Its possible role in the regulation of tobamovirus gene expression and replication is discussed.

3' Untranslated Regions↗

PubMed2004

Opposing effects of ubiquitin conjugation and SUMO modification of PCNA on replicational bypass of DNA lesions in Saccharomyces cerevisiae.

The Rad6-Rad18 ubiquitin-conjugating enzyme complex of Saccharomyces cerevisiae promotes replication through DNA lesions via three separate pathways that include translesion synthesis (TLS) by DNA polymerases zeta (Polzeta) and Poleta and postreplicational repair mediated by the Mms2-Ubc13 ubiquitin-conjugating enzyme and Rad5. Here we report our studies with a proliferating cell nuclear antigen (PCNA) mutation, pol30-119, which results from a change of the lysine 164 residue to arginine. It has been shown recently that following treatment of yeast cells with DNA-damaging agents, the lysine 164 residue of PCNA becomes monoubiquitinated in a Rad6-Rad18-dependent manner and that subsequently this PCNA residue is polyubiquitinated via a lysine 63-linked ubiquitin chain in an Mms2-Ubc13-, Rad5-dependent manner. PCNA is also modified by SUMO conjugation at the lysine 164 residue. Our genetic studies with the pol30-119 mutation show that in addition to conferring a defect in Polzeta-dependent UV mutagenesis and in Poleta-dependent TLS, this PCNA mutation inhibits postreplicational repair of discontinuities that form in the newly synthesized strand across from UV lesions. In addition, we provide evidence for the activation of the RAD52 recombinational pathway in the pol30-119 mutant and we infer that SUMO conjugation at the lysine 164 residue of PCNA has a role in suppressing the Rad52-dependent postreplicational repair pathway.

DNA Damage↗

PubMed2005

Nuclear dynamics of PCNA in DNA replication and repair.

The DNA polymerase processivity factor proliferating cell nuclear antigen (PCNA) is central to both DNA replication and repair. The ring-shaped homotrimeric PCNA encircles and slides along double-stranded DNA, acting as a "sliding clamp" that localizes proteins to DNA. We determined the behavior of green fluorescent protein-tagged human PCNA (GFP-hPCNA) in living cells to analyze its different engagements in DNA replication and repair. Photobleaching and tracking of replication foci revealed a dynamic equilibrium between two kinetic pools of PCNA, i.e., bound to replication foci and as a free mobile fraction. To simultaneously monitor PCNA action in DNA replication and repair, we locally inflicted UV-induced DNA damage. A surprisingly longer residence time of PCNA at damaged areas than at replication foci was observed. Using DNA repair mutants, we showed that the initial recruitment of PCNA to damaged sites was dependent on nucleotide excision repair. Local accumulation of PCNA at damaged regions was observed during all cell cycle stages but temporarily disappeared during early S phase. The reappearance of PCNA accumulation in discrete foci at later stages of S phase likely reflects engagements of PCNA in distinct genome maintenance processes dealing with stalled replication forks, such as translesion synthesis (TLS). Using a ubiquitination mutant of GFP-hPCNA that is unable to participate in TLS, we noticed a significantly shorter residence time in damaged areas. Our results show that changes in the position of PCNA result from de novo assembly of freely mobile replication factors in the nucleoplasmic pool and indicate different binding affinities for PCNA in DNA replication and repair.

Animals↗

PubMed2006

Rad18 regulates DNA polymerase kappa and is required for recovery from S-phase checkpoint-mediated arrest.

We have investigated mechanisms that recruit the translesion synthesis (TLS) DNA polymerase Polkappa to stalled replication forks. The DNA polymerase processivity factor PCNA is monoubiquitinated and interacts with Polkappa in cells treated with the bulky adduct-forming genotoxin benzo[a]pyrene dihydrodiol epoxide (BPDE). A monoubiquitination-defective mutant form of PCNA fails to interact with Polkappa. Small interfering RNA-mediated downregulation of the E3 ligase Rad18 inhibits BPDE-induced PCNA ubiquitination and association between PCNA and Polkappa. Conversely, overexpressed Rad18 induces PCNA ubiquitination and association between PCNA and Polkappa in a DNA damage-independent manner. Therefore, association of Polkappa with PCNA is regulated by Rad18-mediated PCNA ubiquitination. Cells from Rad18(-/-) transgenic mice show defective recovery from BPDE-induced S-phase checkpoints. In Rad18(-/-) cells, BPDE induces elevated and persistent activation of checkpoint kinases, indicating persistently stalled forks due to defective TLS. Rad18-deficient cells show reduced viability after BPDE challenge compared with wild-type cells (but survival after hydroxyurea or ionizing radiation treatment is unaffected by Rad18 deficiency). Inhibition of RPA/ATR/Chk1-mediated S-phase checkpoint signaling partially inhibited BPDE-induced PCNA ubiquitination and prevented interactions between PCNA and Polkappa. Taken together, our results indicate that ATR/Chk1 signaling is required for Rad18-mediated PCNA monoubiquitination. Recruitment of Polkappa to ubiquitinated PCNA enables lesion bypass and eliminates stalled forks, thereby attenuating the S-phase checkpoint.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed2005

Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function.

This review focuses on eukaryotic translesion synthesis (TLS) DNA polymerases, and the emphasis is on Saccharomyces cerevisiae and human Y-family polymerases (Pols) eta, iota, kappa, and Rev1, as well as on Polzeta, which is a member of the B-family polymerases. The fidelity, mismatch extension ability, and lesion bypass efficiencies of these different polymerases are examined and evaluated in the context of their structures. One major conclusion is that, despite the overall similarity of basic structural features among the Y-family polymerases, there is a high degree of specificity in their lesion bypass properties. Some are able to bypass a particular DNA lesion, whereas others are efficient at only the insertion step or the extension step of lesion bypass. This functional divergence is related to the differences in their structures. Polzeta is a highly specialized polymerase specifically adapted for extending primer termini opposite from a diverse array of DNA lesions, and depending upon the DNA lesion, it contributes to lesion bypass in a mutagenic or in an error-free manner. Proliferating cell nuclear antigen (PCNA) provides the central scaffold to which TLS polymerases bind for access to the replication ensemble stalled at a lesion site, and Rad6-Rad18-dependent protein ubiquitination is important for polymerase exchange.

Amino Acid Motifs↗

PubMed2000

The SOS response: recent insights into umuDC-dependent mutagenesis and DNA damage tolerance.

Be they prokaryotic or eukaryotic, organisms are exposed to a multitude of deoxyribonucleic acid (DNA) damaging agents ranging from ultraviolet (UV) light to fungal metabolites, like Aflatoxin B1. Furthermore, DNA damaging agents, such as reactive oxygen species, can be produced by cells themselves as metabolic byproducts and intermediates. Together, these agents pose a constant threat to an organism's genome. As a result, organisms have evolved a number of vitally important mechanisms to repair DNA damage in a high fidelity manner. They have also evolved systems (cell cycle checkpoints) that delay the resumption of the cell cycle after DNA damage to allow more time for these accurate processes to occur. If a cell cannot repair DNA damage accurately, a mutagenic event may occur. Most bacteria, including Escherichia coli, have evolved a coordinated response to these challenges to the integrity of their genomes. In E. coli, this inducible system is termed the SOS response, and it controls both accurate and potentially mutagenic DNA repair functions [reviewed comprehensively in () and also in ()]. Recent advances have focused attention on the umuD(+)C(+)-dependent, translesion DNA synthesis (TLS) process that is responsible for SOS mutagenesis (). Here we discuss the SOS response of E. coli and concentrate in particular on the roles of the umuD(+)C(+) gene products in promoting cell survival after DNA damage via TLS and a primitive DNA damage checkpoint.

Adaptation, Physiological↗

PubMed2005

Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells.

Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polzeta, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy.

Animals↗

PubMed2006

Critical roles for polymerase zeta in cellular tolerance to nitric oxide-induced DNA damage.

Nitric oxide (NO), a signal transmitter involved in inflammation and regulation of smooth muscle and neurons, seems to cause mutagenesis, but its mechanisms have remained elusive. To gain an insight into NO-induced genotoxicity, we analyzed the effect of NO on a panel of chicken DT40 clones deficient in DNA repair pathways, including base and nucleotide excision repair, double-strand break repair, and translesion DNA synthesis (TLS). Our results show that cells deficient in Rev1 and Rev3, a subunit essential for DNA polymerase zeta (Polzeta), are hypersensitive to killing by two chemical NO donors, spermine NONOate and S-nitroso-N-acetyl-penicillamine. Mitotic chromosomal analysis indicates that the hypersensitivity is caused by a significant increase in the level of induced chromosomal breaks. The data reveal the critical role of TLS polymerases in cellular tolerance to NO-induced DNA damage and suggest the contribution of these error-prone polymerases to accumulation of single base substitutions.

Animals↗

PubMed2005

Treatment and prevention of tumor lysis syndrome in children. Experience of Associazione Italiana Ematologia Oncologia Pediatrica.

BACKGROUND: Hyperuricemia and tumor lysis syndrome (TLS) are complications that can arise from treatment of rapidly proliferating and drug-sensitive neoplasms. Clinical trials have shown rasburicase, a recombinant urate oxidase to be more effective than allopurinol for the prevention and treatment of malignancy-associated hyperuricemia. We investigated the safety and efficacy of rasburicase in the AIEOP centers' experience. METHODS: We reviewed the data of 26 children with malignancy at risk for TLS, submitted to treatment (group 1) or prophylaxis (group 2) of acute hyperuricemia with rasburicase (0.20 mg/kg intravenously daily) for a median period of 4 days. RESULTS: Rasburicase produced a significant decrease in uric acid concentrations in all the patients. The control of uric acid levels was obtained in both the groups within 24 h of the first dose with a response rate of 100% (group 1) and 93% (group 2). Normalization of creatinine and phosphorus levels was obtained in 5 and 4 days respectively. Tolerance was excellent without toxicity. CONCLUSIONS: These data confirm that rasburicase is a safe, highly and rapidly effective agent in the treatment and prevention of malignancy-associated acute hyperuricemia and could be considered the treatment of choice to prevent tumor lysis syndrome in children at high risk for this metabolic complication.

Acute Kidney Injury↗