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PubMed1991

Monomerization of RepA dimers by heat shock proteins activates binding to DNA replication origin.

DnaK is a major heat shock protein of Escherichia coli and the homolog of hsp70 in eukaryotes. We demonstrate the mechanism by which DnaK and another heat shock protein, DnaJ, render the plasmid P1 initiator RepA 100-fold more active for binding to the P1 origin of replication. Activation is the conversion of RepA dimers into monomers in an ATP-dependent reaction and the monomer form binds with high affinity to oriP1 DNA. Reversible chemical denaturants also convert RepA dimers to monomers and simultaneously activate oriP1 DNA binding. Increasing protein concentration converts monomers to dimers and deactivates RepA. Based on our data and previous work, we present a model for heat shock protein action under normal and stress conditions.

Adenosine Triphosphate↗
PubMed2000

Gastric mucosal cell proliferation in ethanol-induced chronic mucosal injury is related to oxidative stress and lipid peroxidation in rats.

The oxygen free radicals-induced lipid peroxidation (LP) has been implicated in the pathogenesis of acute ethanol-induced gastric mucosal lesions. However, the role of LP in the generation of chronic gastric mucosal injury is unknown. We have developed a model of chronic mucosal injury induced by continuous ethanol ingestion for 5 days and characterized by marked alterations in plasma membranes from gastric mucosa. Therefore, LP was evaluated in this experimental model. Indicators of peroxidative activity, mucosal glutathione content, thymidine kinase activity (an index of cell proliferation), and histamine H2-receptor (H2R) binding constants were quantified in animals undergoing gastric mucosal damage. The effect of famotidine, a H2R antagonist that readily ameliorates the chronic mucosal injury, was also tested. Increased free radicals and LP levels were detected during gastritis; however, a second, higher peak of LP was noted in mucosal plasma membranes after ethanol withdrawal (recovery period). This further increase of LP coincided with active cell proliferation, decreased mucosal glutathione levels, and diminished specific cimetidine binding by H2R. Administration of famotidine accelerated the mucosal proliferative process, inducing the second lipoperoxidative episode sooner, and preserved the content of glutathione. In addition, LP correlated directly with cell proliferation and inversely with mucosal membrane cimetidine binding. In conclusion, LP seems to be involved in chronic ethanol-induced gastric mucosal injury. However, a further enhancement of plasma membrane LP occurred, associated with increased DNA synthesis and diminished cimetidine binding by membrane H2R. Therefore, increased LP could also participate in the compensatory mucosal proliferation initiated after ethanol withdrawal.

Animals↗
PubMed1997

Rapid evolution of viral RNA genomes.

Mutation rates during RNA virus replication are several orders of magnitude larger than those operating during replication of cellular DNA. This results in the continuous generation of mutant genomes and in their rating in competition with other variants present and arising in the population. The dynamic mutant distributions that constitute RNA virus populations are termed quasispecies. This concept has facilitated links between population genetics and virology and has a number of important implications for viral pathogenesis and the control of viral disease. One of them is that the mutant spectra in RNA viruses constitute large reservoirs of genetic and phenotypic variants with potentially altered biological properties. Individual mutants kept in a low proportion under a set of environmental conditions may become dominant following an environmental change. Relevant to this review are possible links between the alteration of quasispecies distributions and nutritional deficiencies and oxidative stress in cells. In addition to being a possible mechanism of viral pathogenesis, oxidative stress, and other environmental modifications resulting from nutritional imbalances, may promote population disequilibrium in replicating viruses. In particular, the increased mutagenesis mediated by oxidative DNA damage could also affect replicating RNA and integrated provirus, extending the mutant repertoire of viruses. Also, the impairment of humoral and cellular immune functions may delay or prevent viral clearance, leading to an expanded representation of viral mutants in the infected organism. Thus, nutritional deficiencies are a potential source of viral mutants with altered biological properties.

Biological Evolution↗
PubMed1992

Involvement of cellular division cycle in the susceptibility of Escherichia coli to cold- and osmotic-shock.

Susceptibility of Escherichia coli to cold-shock, osmotic-shock and cold-osmotic-shock has been evaluated throughout the cellular division cycle for a variety of generation time. Two periods of sensitisation were detected. The first of these was towards cold-shock which occurred 60 min prior to cell division and might correspond to initiation of DNA replication. The second period of sensitisation was towards both cold-, osmotic- and cold-osmotic-shock and occurred immediately prior to and during cell division. Patterns and extents of sensitisation towards each of these three stresses during the second period were suggestive of a common sensitising event associated with constriction of the cell and separation.

Cell Cycle↗
PubMed2002

A method for assaying the sensitivity of Drosophila replication checkpoint mutants to anti-cancer and DNA-damaging drugs.

In multi-cellular organisms, failure to properly regulate cell-cycle progression can result in inappropriate cell death or uncontrolled cell division leading to tumor formation. To guard against such events, conserved regulatory mechanisms called "checkpoints" block progression into mitosis in response to DNA damage and incomplete replication, as well as in response to other signals. Checkpoint mutants in organisms as diverse as yeast and humans are sensitive to various chemical agents that inhibit DNA replication or cause DNA damage. This phenomenon is the primary rationale for chemotherapy, which uses drugs that preferentially target tumor cells with compromised checkpoints. In this study, we demonstrate the use of Drosophila checkpoint mutants as a system for assaying the effects of various DNA-damaging and anti-cancer agents in a developing multicellular organism. Dwee1, grp and mei-41 are genes that encode kinases that function in the DNA replication checkpoint. We tested zygotic mutants of each gene for sensitivity to the DNA replication inhibitor hydroxyurea (HU), methyl methanosulfonate (MMS), ara-C, cisplatin, and the oxygen radical generating compound paraquat. The mutants show distinct differences in their sensitivity to each of the drugs tested, suggesting an underlying complexity in the responses of individual checkpoint genes to genotoxic stress.

Animals↗
PubMed1998

Suppressors of cdc25p overexpression identify two pathways that influence the G2/M checkpoint in fission yeast.

Checkpoints maintain the order of cell-cycle events. At G2/M, a checkpoint blocks mitosis in response to damaged or unreplicated DNA. There are significant differences in the checkpoint responses to damaged DNA and unreplicated DNA, although many of the same genes are involved in both responses. To identify new genes that function specifically in the DNA replication checkpoint pathway, we searched for high-copy suppressors of overproducer of Cdc25p (OPcdc25(+)), which lacks a DNA replication checkpoint. Two classes of suppressors were isolated. One class includes a new gene encoding a putative DEAD box helicase, suppressor of uncontrolled mitosis (sum3(+)). This gene negatively regulates the cell-cycle response to stress when overexpressed and restores the checkpoint response by a mechanism that is independent of Cdc2p tyrosine phosphorylation. The second class includes chk1(+) and the two Schizosaccharomyces pombe 14-3-3 genes, rad24(+) and rad25(+), which appear to suppress the checkpoint defect by inhibiting Cdc25p. We show that rad24Delta mutants are defective in the checkpoint response to the DNA replication inhibitor hydroxyurea at 37 degrees and that cds1Delta rad24Delta mutants, like cds1Delta chk1Delta mutants, are entirely checkpoint deficient at 29 degrees. These results suggest that chk1(+) and rad24(+) may function redundantly with cds1(+) in the checkpoint response to unreplicated DNA.

Amino Acid Sequence↗
PubMed2004

Induction of renal oxidative stress and cell proliferation response by ferric nitrilotriacetate (Fe-NTA): diminution by soy isoflavones.

Ferric nitrilotriacetate (Fe-NTA) is a known potent nephrotoxic agent. In this communication, we report the chemopreventive effect of soy isoflavones on renal oxidative stress, toxicity and cell proliferation response in Wistar rats. Fe-NTA (9 mg Fe/kg body weight, intraperitoneally) enhances gamma-glutamyl transpeptidase, renal lipid peroxidation, xanthine oxidase and hydrogen peroxide (H2O2) generation with reduction in renal glutathione content, antioxidant enzymes, viz., glutathione peroxidase, glutathione reductase, catalase, glucose-6-phosphate dehydrogenase and phase-II metabolising enzymes such as glutathione-S-transferase and quinone reductase. Fe-NTA treatment also induced tumor promotion markers, viz., ornithine decarboxylase (ODC) activity and thymidine [3H] incorporation into renal DNA. A sharp elevation in the levels of blood urea nitrogen and serum creatinine has also been observed. Treatment of rats orally with soy isoflavones (5 mg/kg body weight and 10 mg/kg body weight) resulted in significant decreases in gamma-glutamyl transpeptidase, lipid peroxidation, xanthine oxidase, H2O2 generation, blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P < 0.001). Renal glutathione content (P < 0.01), glutathione metabolizing enzymes (P < 0.001) and antioxidant enzymes were also returned to normal levels (P < 0.001). Thus, our data suggest that soy isoflavones may be used as an effective chemopreventive agent against Fe-NTA-mediated renal oxidative stress, toxicity and cell proliferation response in Wistar rats.

Administration, Oral↗
PubMed2004

Adaptive mutation and amplification in Escherichia coli: two pathways of genome adaptation under stress.

The neo-Darwinists suggested that evolution is constant and gradual, and thus that genetic changes that drive evolution should be too. However, more recent understanding of phenomena called adaptive mutation in microbes indicates that mutation rates can be elevated in response to stress, producing beneficial and other mutations. We review evidence that, in Escherichia coli, two separate mechanisms of stress-induced genetic change occur that revert a lac frameshift allele allowing growth on lactose medium. First, compensatory frameshift ("point") mutations occur by a mechanism that includes DNA double-strand breaks and (we have suggested) their error-prone repair. Point mutation requires induction of the RpoS-dependent general stress response, and the SOS DNA damage response leading to upregulation of the error-prone DNA polymerase DinB (Pol IV), and occurs during a transient limitation of post-replicative mismatch repair activity. A second mechanism, adaptive amplification, entails amplification of the leaky lac allele to 20-50 tandem repeats. These provide sufficient beta-galactosidase activity for growth, thereby apparently deflecting cells from the point mutation pathway. Unlike point mutation, amplification neither occurs in hypermutating cells nor requires SOS or DinB, but like point mutation, amplification requires the RpoS-dependent stress response. Similar processes are being found in other bacterial systems and yeast. Stress-induced genetic changes may underlie much of microbial evolution, pathogenesis and antibiotic resistance, and also cancer formation, progression and drug resistance.

Adaptation, Biological↗
PubMed1995

The effect of implantation of osmotic pumps on rat thyroid hormone and testosterone levels in the plasma, an implication for tissue 'S' phase studies.

In order to monitor the effect of the procedures required to s.c. implant osmotic pumps into rats on plasma thyroid and testosterone hormone levels, male Fischer 344 rats (8-10 weeks old) were divided into six groups of 10 rats and the groups treated in the following manner: (1) controls housed 5 per cage; (2) controls housed individually; (3) animals anaesthetised for surgery and individually housed; (4) anaesthetised, sham operated and individually housed; (5) anaesthetised, s.c. implanted with osmotic pumps containing saline and individually housed; (6) anaesthetised, s.c. implanted with osmotic pumps containing 5-bromo 2-deoxyuridine (BRDU) and individually housed. Four days after performing the surgery the study was terminated and the level of hormones in the plasma determined by radio immunoassay (RIA). Tri-iodothyronine (T3) and thyroxine (T4) plasma levels (free and total) were significantly decreased with each additional step in the procedure used for the s.c. implantation of an osmotic pump containing BRDU, when compared with the individually housed controls. Similarly, testosterone plasma levels were significantly decreased by the s.c. implantation of osmotic pumps, implying a 'stress' response might occur following implantation. These observations might need to be considered by investigators when performing toxicological research which, as part of the study, uses osmotic pumps for the delivery of the nucleotide precursor required for monitoring cells in 'S' phase.

Animals↗
PubMed2002

E2F mediates sustained G2 arrest and down-regulation of Stathmin and AIM-1 expression in response to genotoxic stress.

Exposure of cells to genotoxic agents results in activation of checkpoint pathways leading to cell cycle arrest. These arrest pathways allow repair of damaged DNA before its replication and segregation, thus preventing accumulation of mutations. The tumor suppressor retinoblastoma (RB) is required for the G(1)/S checkpoint function. In addition, regulation of the G(2) checkpoint by the tumor suppressor p53 is RB-dependent. However, the molecular mechanism underlying the involvement of RB and its related proteins p107 and p130 in the G(2) checkpoint is not fully understood. We show here that sustained G(2)/M arrest induced by the genotoxic agent doxorubicin is E2F-dependent and involves a decrease in expression of two mitotic regulators, Stathmin and AIM-1. Abrogation of E2F function by dominant negative E2F abolishes the doxorubicin-induced down-regulation of Stathmin and AIM-1 and leads to premature exit from G(2). Expression of the E7 papilloma virus protein, which dissociates complexes containing E2F and RB family members, also prevents the down-regulation of these mitotic genes and leads to premature exit from G(2) after genotoxic stress. Furthermore, genotoxic stress increases the levels of nuclear E2F-4 and p130 as well as their in vivo binding to the Stathmin promoter. Thus, functional complexes containing E2F and RB family members appear to be essential for repressing expression of critical mitotic regulators and maintaining the G(2)/M checkpoint.

3T3 Cells↗
PubMed2004

Mitochondria damage checkpoint in apoptosis and genome stability.

Mitochondria perform multiple cellular functions including energy production, cell proliferation and apoptosis. Studies described in this paper suggest a role for mitochondria in maintaining genomic stability. Genomic stability appears to be dependent on mitochondrial functions involved in maintenance of proper intracellular redox status, ATP-dependent transcription, DNA replication, DNA repair and DNA recombination. To further elucidate the role of mitochondria in genomic stability, I propose a mitochondria damage checkpoint (mitocheckpoint) that monitors and responds to damaged mitochondria. Mitocheckpoint can coordinate and maintain proper balance between apoptotic and anti-apoptotic signals. When mitochondria are damaged, mitocheckpoint can be activated to help cells repair damaged mitochondria, to restore normal mitochondrial function and avoid production of mitochondria-defective cells. If mitochondria are severely damaged, mitocheckpoint may not be able to repair the damage and protect cells. Such an event triggers apoptosis. If damage to mitochondria is continuous or persistent such as damage to mitochondrial DNA resulting in mutations, mitocheckpoint may fail which can lead to genomic instability and increased cell survival in yeast. In human it can cause cancer. In support of this proposal we provide evidence that mitochondrial genetic defects in both yeast and mammalian systems lead to impaired DNA repair, increased genomic instability and increased cell survival. This study reveals molecular genetic mechanisms underlying a role for mitochondria in carcinogenesis in humans.

Adenosine Triphosphate↗
PubMed2005

Regulation of growth arrest in senescence: telomere damage is not the end of the story.

After a limited number of divisions, most eukaryotic cells grown in culture will undergo a terminal growth arrest called cellular senescence. This growth arrest is thought to be a consequence of progressive telomere shortening that occurs due to incomplete DNA replication of the chromosome ends. In addition, cellular senescence can also be induced by a number of environmental stresses and signaling imbalances which are independent of telomere shortening. The cyclin dependent kinase inhibitors p21 and p16(INK4a) have been shown to execute and maintain the cell cycle arrest in senescence but the nature of the signals that cause upregulation of these inhibitors in senescent cells are only now starting to be discovered. Here we will review the current literature that leads us to propose a model how independent signals activate distinct signaling pathways to regulate p21 and p16(INK4a) levels in senescent cells.

Animals↗
PubMed2006

Life is degrading--thanks to some zomes.

Three structurally related protein complexes, the COP9 signalosome, the proteasome lid, and the eukaryotic translation initiation factor 3, are revealing new insights into developmental processes and into cell cycle control in healthy cells and cells exposed to genotoxic stress. Newly discovered cullin-RING E3 ubiquitin ligases assembled on the CUL4 platform may provide links between DNA replication, chromatin, and proteolysis.

Animals↗
PubMed2001

Topoisomerase I-mediated DNA damage.

Topoisomerase I is a ubiquitous and essential enzyme in multicellular organisms. It is involved in multiple DNA transactions including DNA replication, transcription, chromosome condensation and decondensation, and probably DNA recombination. Besides its activity of DNA relaxation necessary to eliminate torsional stresses associated with these processes, topoisomerase I may have other functions related to its interaction with other cellular proteins. Topoisomerase I is the target of the novel anticancer drugs, the camptothecins. Recently a broad range of physiological and environmentally-induced DNA modifications have also been shown to poison topoisomerases. This review summarizes the various factors that enhance or suppress top1 cleavage complexes and discusses the significance of such effects. We also review the different mechanisms that have been proposed for the repair of topoisomerase I-mediated DNA lesions.

Animals↗
PubMed2001

Role of cyclins in epithelial response to oxidants.

Oxidants are involved in a large variety of pulmonary diseases. Among the various cell types that compose the respiratory system, the epithelial cells appear to be a major target for oxidative stress. When cells are exposed to DNA-damaging agents such as oxidants, a feedback control is activated that acts as a brake on the cell cycle to inhibit entry into the S phase until DNA repair is completed. Progression through the G1 phase and the G1-S transition involves sequential assembly and activation of key regulators of the cell cycle machinery, the cyclin-dependent kinases (CDKs). Activity of the CDKs is regulated by several mechanisms, which include the CDK inhibitors (CKIs). The CKI p21(CIP1) appears to play an important role in the response of epithelial cells to oxidants.

Animals↗
PubMed2004

Apoptotic topoisomerase I-DNA complexes induced by oxygen radicals and mitochondrial dysfunction.

Topoisomerase I (Top1) is expressed throughout the cell cycle. Top1 forms reversible and transient DNA cleavage complexes as it relaxes DNA supercoiling generated by transcription and replication. Recent findings indicate that mechanistically different inducers of apoptosis, arsenic trioxide, staurosporine and etoposide, which are inactive on purified Top1, induce Top1 cleavage complexes. These apoptotic Top1 cleavage complexes result from oxidative DNA lesions generated by reactive oxygen species during apoptosis. Their functional role could be to directly fragment chromatin and to further activate (amplify) apoptotic pathways.

Animals↗
PubMed1997

Lead/cytokine-mediated oxidative DNA damage in cultured mouse hepatocytes.

Hepatocytes exposed to the cytokines tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma), in combination with a nontoxic dose of lead (Pb), exhibited significantly greater cytotoxicity compared to cytokine-treated hepatocytes after 24 hr treatment. Concentrations of Pb which interact with the cytokines to cause cytotoxicity stimulated hepatocytes cultured at this high cell density (63,830 cells/cm2) to undergo active DNA synthesis. DNA synthesis was also observed in hepatocytes plated at a low cell densities (21,276 cells/cm2) and these cells were sensitive to the toxic effects of the cytokines in the absence of Pb. Under conditions of active DNA synthesis, induced by either Pb or cell density, cytokine-induced toxicity appeared to be the result of extensive DNA fragmentation. Both DNA fragmentation and cytotoxicity were inhibited by treatment with an antioxidant mixture. Pb potentiated cytokine-induced oxidative stress within hepatocytes as indicated by decreased intracellular glutathione (GSH) and increased efflux of oxidized glutathione (GSSG) prior to cytotoxicity. The combination of cytokines and Pb also caused a significant decline in intracellular ATP concentrations prior to the onset of cytotoxicity. ATP concentrations were not altered by treatment with Pb or cytokines alone. Pb treatment did not alter total protein synthesis within hepatocytes. These results indicate that the cytotoxic interaction between Pb and the cytokines TNFalpha and IFNgamma may be mediated by oxidative DNA damage resulting from cytokine-induced oxidative stress and stimulation of mitogenic signals.

Adenosine Triphosphate↗