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PubMed2005

Mrc1 is required for normal progression of replication forks throughout chromatin in S. cerevisiae.

Mrc1 associates with replication forks, where it transmits replication stress signals and is required for normal replisome pausing in response to nucleotide depletion. Mrc1 also plays a poorly understood role in DNA replication, which appears distinct from its role in checkpoint signaling. Here, we demonstrate that Mrc1 functions constitutively to promote normal replication fork progression. In mrc1Delta cells, replication forks proceed slowly throughout chromatin, rather than being specifically defective in pausing and progression through loci that impede fork progression. Analysis of genetic interactions with Rrm3, a DNA helicase required to resolve paused forks, indicates that Mrc1 checkpoint signaling is dispensable for the resolution of stalled replication forks and suggests that replication forks lacking Mrc1 create DNA damage that must be repaired by Rrm3. These findings elucidate a central role for Mrc1 in normal replisome function, which is distinct from its role as a checkpoint mediator, but nevertheless critical to genome stability.

Cell Cycle Proteins↗
PubMed1992

A possible factor in genetic instability of cancer cells: stress-induced secreted proteins lead to decrease in replication fidelity.

Ultraviolet irradiation triggers a response in mammalian cells known as the UV response. Part of the UV response forms the enhanced synthesis of various extracellular proteins able to transmit the response to non-irradiated cells. Because several cancer-prone syndromes with enhanced genetic instability also have an enhanced synthesis of the same set of proteins without prior stimulation it is possible that induction of these stress responsive proteins may be involved in the process of carcinogenesis and genetic instability. To test this hypothesis mouse T lymphoma cells, GRSL13, were treated with the conditioned medium of UV-induced cells under various experimental conditions. Overall the mutation rate is enhanced 1.8-fold (P < 0.01). However, the degree of enhancement is strongly influenced by culture conditions. UV-induced factors only lead to an enhanced mutation rate when cells, both for the production and response to those factors, originate from a similar cell density. In addition, it was found that fresh medium interferes with this response. To eliminate the hindrance of these factors on the effect of the conditioned medium on the mutation rate, serum-starved cells at high density were treated with serum-free medium derived from high-density UV-irradiated cultures. Using these conditions a 2.8-fold (P < 0.002) enhancement of the mutation rate was found. Fluctuation analysis indicated that the enhancement is 10-fold during the first five generations after treatment. UV-induced factors have also been found to induce cell growth, and the degree of induction was linearly correlated with the enhancement in mutation rate. These experiments are in agreement with the hypothesis that induction of stress responses leads to genetic instability.

Animals↗
PubMed2006

The nitrosative stress response of Staphylococcus aureus is required for resistance to innate immunity.

Staphylococcus aureus is a highly virulent human pathogen with an extensive array of strategies to subvert the innate immune response. An important aspect of innate immunity is the production of the nitrogen monoxide radical (Nitric Oxide, NO.). Here we describe an adaptive response to nitrosative stress that allows S. aureus to replicate at high concentrations of NO.. Microarray analysis revealed 84 staphylococcal genes with significantly altered expression following NO. exposure. Of these, 30 are involved with iron-homeostasis, potentially under the control of the Fur regulator. Another seven induced genes are involved in hypoxic/fermentative metabolism, including the flavohaemoprotein, Hmp. The SrrAB two-component system has been shown to regulate the expression of many of the NO.-induced metabolic genes. Indeed, inactivation of hmp, srrAB and fur resulted in heightened NO. sensitivity. Hmp was responsible for c. 90% of measurable staphylococcal NO. consumption and therefore critical for efficient NO. detoxification. While SrrAB was required for maximal hmp expression, srrAB mutants still exhibited significant NO. scavenging and NO.-dependent induction of hmp. Yet S. aureus lacking SrrAB were more sensitive to nitrosative stress than hmp mutants, indicating that the contribution of SrrAB to NO. resistance extends beyond the regulation of hmp expression. Both Hmp and SrrAB were required for full virulence in a murine sepsis model, however, only the attenuation of the hmp mutant was restored by the abrogation of host NO. production. Thus, the S. aureus Hmp protein has evolved to serve as an iNOS-dependent virulence determinant.

Animals↗
PubMed2003

Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with posttraumatic stress disorder.

BACKGROUND: Larger heart rate responses to sudden, loud (startling) tones represent one of the best-replicated psychophysiologic markers for posttraumatic stress disorder (PTSD). This abnormality may be a pretrauma vulnerability factor, ie, it may have been present prior to the event's occurrence and increased the individual's likelihood of developing PTSD on traumatic exposure. Alternately, it may be an acquired PTSD sign, ie, it may have developed after the traumatic exposure, along with the PTSD. Studying identical twins discordant for traumatic exposure offers an opportunity to resolve these competing origins. METHODS: Subjects included pairs of Vietnam combat veterans and their non-combat-exposed, monozygotic twins. Combat veterans were diagnosed as having current PTSD (n = 50) or non-PTSD (ie, never had) (n = 53). All subjects listened to a series of 15 sudden, loud tone presentations while heart rate, skin conductance, and orbicularis oculi electromyogram responses were measured. RESULTS: Consistent with previous reports, averaged heart rate responses to the tones were larger in Vietnam combat veterans with PTSD. These larger responses were not shared by their non-combat-exposed co-twins, whose responses were similar to those of the non-PTSD combat veterans and their non-combat-exposed co-twins. This result remained significant after adjusting for a number of potentially confounding factors. CONCLUSIONS: The results suggest that larger heart rate responses to sudden, loud tones represent an acquired sign of PTSD rather than a familial vulnerability factor.

Acoustic Stimulation↗
PubMed2005

Hepatitis C virus (HCV) constitutively activates STAT-3 via oxidative stress: role of STAT-3 in HCV replication.

The hepatitis C virus (HCV) causes chronic hepatitis, which often results in liver cirrhosis and hepatocellular carcinoma. We have previously shown that HCV nonstructural proteins induce activation of STAT-3 via oxidative stress and Ca2+ signaling (G. Gong, G. Waris, R. Tanveer, and A. Siddiqui, Proc. Natl. Acad. Sci. USA 98:9599-9604, 2001). In this study, we focus on the signaling pathway leading to STAT-3 activation in response to oxidative stress induced by HCV translation and replication activities. Here, we demonstrate the constitutive activation of STAT-3 in HCV replicon-expressing cells. The HCV-induced STAT-3 activation was inhibited in the presence of antioxidant (pyrrolidine dithiocarbamate) and Ca2+ chelators (BAPTA-AM and TMB-8). Previous studies have shown that maximum STAT-3 transactivation requires Ser727 phosphorylation in addition to tyrosine phosphorylation. Using a series of inhibitors and dominant negative mutants, we show that HCV-induced activation of STAT-3 is mediated by oxidative stress and influenced by the activation of cellular kinases, including p38 mitogen-activated protein kinase, JNK, JAK-2, and Src. Our results also suggest a potential role of STAT-3 in HCV RNA replication. We also observed the constitutive activation of STAT-3 in the liver biopsy of an HCV-infected patient. These studies provide an insight into the mechanisms by which HCV induces intracellular events relevant to liver pathogenesis associated with the viral infection.

Cell Line, Tumor↗
PubMed2006

ATRIP associates with replication protein A-coated ssDNA through multiple interactions.

The ATR (ATM- and rad3-related)-mediated checkpoint pathway has a crucial role in regulating the cellular responses to DNA damage and DNA-replication stress. ATRIP (ATR-interacting protein), the regulatory partner of ATR, binds directly to replication protein A (RPA)-coated ssDNA and enables the ATR-ATRIP complex to recognize this DNA damage-induced structure. Here, we show that ATRIP associates with RPA-ssDNA through multiple interactions. Two major RPA-ssDNA-interacting domains of ATRIP were mapped to the regions flanking the conserved coiled-coil domain. In contrast to a recent article, we found that ATRIP mutants lacking the N terminus retained the ability to bind to RPA-ssDNA, suggesting that the multiple interactions between ATRIP and RPA-ssDNA may function redundantly in the recruitment of ATR-ATRIP. Unexpectedly, one internal region of ATRIP exhibited affinity to ssDNA, suggesting that ATRIP may interact with ssDNA in the ATRIP-RPA-ssDNA complex. Also, the N terminus of ATRIP associated with RPA-ssDNA in two distinct ways, indicating a dynamic and regulated association between ATRIP and RPA-ssDNA.

Adaptor Proteins, Signal Transducing↗
PubMed2004

UV-induced ataxia-telangiectasia-mutated and Rad3-related (ATR) activation requires replication stress.

Ataxia-telangiectasia-mutated and Rad3-related (ATR) plays an essential role in the maintenance of genome integrity and cell viability. The kinase is activated in response to DNA damage and initiates a checkpoint signaling cascade by phosphorylating a number of downstream substrates including Chk1. Unlike ataxia-telangiectasia-mutated (ATM), which appears to be mainly activated by DNA double-strand breaks, ATR can be activated by a variety of DNA damaging agents. However, it is still unclear what triggers ATR activation in response to such diverse DNA lesions. One model proposes that ATR can directly recognize DNA lesions, while other recent data suggest that ATR is activated by a common single-stranded DNA (ssDNA) intermediate generated during DNA repair. In this study, we show that UV lesions do not directly activate ATR in vivo. In addition, ssDNA lesions created during the repair of UV damage are also not sufficient to activate the ATR-dependent pathway. ATR activation is only observed in replicating cells indicating that replication stress is required to trigger the ATR-mediated checkpoint cascade in response to UV irradiation. Interestingly, H2AX appears to be required for the accumulation of ATR at stalled replication forks. Together our data suggest that ssDNA at arrested replication forks recruits ATR and initiates ATR-mediated phosphorylation of H2AX and Chk1. Phosphorylated H2AX might further facilitate ATR activation by stabilizing ATR at the sites of arrested replication forks.

Cell Cycle Proteins↗
PubMed1997

The nuclear matrix: a target for heat shock effects and a determinant for stress response.

The nuclear matrix organizes nuclear DNA into operational DNA domains for replication, transcription, and repair. The proteins of the nuclear matrix are among the most thermal labile proteins in the cell, undergoing denaturation at 43 degrees C to 45 degrees C. Heat-shock-induced protein denaturation results in the aggregation of proteins to the nuclear matrix. As many as 100 protein changes have been observed as a result of this aggregation. Protein aggregation with the nuclear matrix is associated with the disruption of nuclear matrix-dependent DNA replication, DNA transcription, hnRNA processing, and DNA repair. Disruptions of these processes lead to cell death. Nuclear matrix protein changes affect these processes by inhibiting DNA supercoiling ability and inhibiting the access to matrix-associated DNA. Heat-shock proteins are believed to bind denatured proteins and either prevent aggregation or render aggregates more readily dissociable. The nuclear matrix appears to be a target for the detrimental effects of heat shock and hsp70 serves to protect against such effects. However, the nuclear matrix may be involved in the pre- and post-heat shock expression of hsp70. We have found a heat-inducible MAR covering the promoter region of murine hsp70.3, implying that changes in matrix association are needed for hsp70 expression. However, the hsp70.1, 70.3, and hsc70t gene family is organized as an active gene with respect to the nuclear matrix. Thus, it may be that heat-inducible genes have a unique matrix-dependent organization. The work presented in this review implies that the nuclear matrix is a target for the lethal effects of heat and is also a determinant in the protective expression of heat-shock genes.

Animals↗
PubMed1988

Activation of human immunodeficiency virus type 1 by DNA damage in human cells.

Recent studies indicate that human immunodeficiency virus type 1 (HIV) gene expression can be dramatically enhanced by certain heterologous viral and chemical agents, implicating these as potential reactivating agents of latent virus infection. A common denominator shared by these agents is their ability to cause stress responses in cells. In an effort to determine whether stress responses affect HIV gene expression, we examined the effects of ultraviolet light (UV) and mitomycin C, on HIV gene expression as well as on viral growth and development. We demonstrate that these agents enhance HIV gene expression up to 150-fold. These levels are similar to those obtained by the tat gene product, the HIV trans-activating factor responsible for enhancing viral gene expression. The increase in gene expression after UV irradiation appears to require transcription but not de novo protein synthesis, and correlates with an accumulation of stable mRNA. Most importantly, UV irradiation of human T-cells prior to viral infection significantly shortens the viral growth cycle. Apparently, UV-induced cellular stress is highly conducive for viral replication and growth. We further demonstrate that even direct sunlight can activate HIV gene expression. These results demonstrate that DNA damaging agents, and perhaps other agents which elicit SOS-like stress responses in mammalian cells, can activate HIV expression thereby enhancing viral replication and development.

Acetyltransferases↗
PubMed1996

Vaccinia virus replication is independent of cellular HSP72 expression which is induced during virus infection.

HSP72 is dramatically induced in the ovaries of vaccinia virus (VV)-infected mice and associates with VV proteins. In order to investigate the role of HSP72 during vaccinia virus replication, we have constructed a recombinant vaccinia virus encoding the major inducible cellular HSP72 (VV-HSP72+) and examined the replication characteristics of this virus. VV-HSP72+ exhibited growth kinetics identical to and peak titers very similar to those of control viruses, both in vitro and in vivo. In particular, replication of VV-HSP72+ was identical to that of control viruses in the HSP72-negative cell line Y3.Ag.1.2.3, and overexpression of HSP72 had no effect on the virulence of VV infection in normal or immunocompromised mice. We conclude that while VV infection results in the induction of the major inducible 72-kDa HSP, VV replication proceeds normally in the absence of this protein. It is unclear whether another celluar chaperone is required to facilitate virus replication in place of HSP72 in Y3.Ag.1.2.3 cells or whether HSP expression plays no role in virus replication, but is simply a component of the generalized stress response to virus infection.

Animals↗
PubMed2006

The DNA damage response arouses the immune system.

Although there is considerable knowledge of how DNA damage triggers cell cycle arrest, DNA repair, and apoptosis, little was known about its potential role in immune responses. Recently, we showed that genotoxic stress and stalled DNA replication forks induce the expression of ligands for the NKG2D receptor found in natural killer cells and certain T cells, cell types that are able to attack tumor cells. Chronic activation of this response in tumor cells may contribute to immune recognition, but it also imposes a selection mechanism for immune escape and malignant progression. This unique arm of the DNA damage response may have implications for understanding therapeutic responses, many of which induce the DNA damage response, and for designing more effective regimens to treat cancer.

Animals↗
PubMed2004

Inhibition of bovine herpesvirus-4 replication in endothelial cells by arsenite.

The effect of arsenite pretreatment on bovine herpesvirus-4 (BHV-4) replication in bovine arterial endothelial (BAE) cells was studied. BHV-4 infectivity, including IE-2 expression, DNA replication and viral yield, were significantly reduced at nontoxic concentrations of arsenite in which cellular DNA synthesis or cell viability of BAE cells were not affected under resting and confluent conditions. This effect was accompanied by the induction of heat shock protein 70 (HSP70) and an interrupted cell cycle (causing cell cultures to accumulate at the S and G2/M phases). Actinomycin D inhibited the induction of HSP70 and reduced arsenite antiviral activity. In conclusion, cellular stress response induced by arsenite in BAE cells inhibited replication of BHV-4, and probably resulted from the induction of HSP70 and interference of cell cycle progression.

Animals↗
PubMed1997

Phenotypic and evolutionary adaptation of a model bacterial system to stressful thermal environments.

We studied both phenotypic and evolutionary adaptation to various thermal environments using the bacterium Escherichia coli as an experimental model system. We determined that 42 degrees C was stressful to a bacterial clone adapted to 37 degrees C, based on reductions in both absolute and competitive fitness, as well as induction of a heat stress response. This clone was also used to found replicated populations that were propagated for thousands of generations under several different thermal regimes, including 42 degrees C. Evolutionary adaptation of the populations to 42 degrees C resulted in an increase in both absolute and relative fitness at that temperature, measured respectively as an increase in the number of descendants (and their biovolume) and in competitive ability relative to the ancestral clone. The replicated experimental lineages achieved their evolutionary improvement by several distinct pathways, which produced differential preadaptation to a non-stressful nutrient environment. Adaptation to this stressful temperature entailed neither a change in the ancestral thermal niche nor any pronounced trade-offs in fitness within the thermal niche, contrary to a priori predictions. This study system was several important advantages for evaluating hypotheses concerning the effects of stress on phenotypic and evolutionary adaptation, including the ability to obtain lineages that have evolved in controlled and defined environments, to make direct measurements of fitness and to quantify the degree of stress imposed by different environments.

Adaptation, Physiological↗
PubMed2002

Macrophages inhibit Salmonella typhimurium replication through MEK/ERK kinase and phagocyte NADPH oxidase activities.

Host responses during the later stages of Salmonella-macrophage interactions are critical to controlling infection but have not been well characterized. After 24 h of infection, nearly half of interferon-gamma-primed murine RAW 264.7 macrophage-like cells infected by Salmonella enterica serovar Typhimurium contained filamentous bacteria. Bacterial filamentation indicates a defect in completing replication and has been previously observed in bacteria responding to a variety of stresses. To understand whether macrophage gene expression was responsible for this effect on Salmonella Typhimurium replication, we used gene arrays to profile interferon-gamma-primed RAW 264.7 cell gene expression following infection. We observed an increase in MEK1 kinase mRNA at 8 h, an increase in MEK protein at 24 h, and measured phosphorylation of MEK's downstream target kinase, ERK1/2, throughout the 24-h infection period. Treatment of cells with MEK kinase inhibitors significantly reduced numbers of filamentous bacteria observed within macrophages after 24 h and increased the number of intracellular colony-forming units. Phagocyte NADPH oxidase inhibitors and antioxidants also significantly reduced bacterial filamentation. Either MEK kinase or phagocyte oxidase inhibitors could be added 4-8 h after infection and still significantly decrease bacterial filamentation. Oxidase activity appears to mediate bacterial filamentation in parallel to MEK kinase signaling, while inducible nitric-oxide synthase inhibitors had no significant effect on bacterial morphology. In summary, Salmonella Typhimurium infection of interferon-gamma-primed macrophages triggers a MEK kinase cascade at later infection times, and both MEK kinase and phagocyte NADPH oxidase activity impair bacterial replication. These two signaling pathways mediate a host bacteriostatic pathway and may play an important role in innate host defense against intracellular pathogens.

Animals↗
PubMed1999

Phenotypic modulation by intracellular bacterial pathogens.

Microorganisms have the capacity to sense their environment and to respond to it by alteration in gene expression and protein synthesis. Two-dimensional electrophoresis (2-DE) provides a powerful tool to examine the global response in bacterial protein synthesis upon exposure to different environmental signals. One of the most complex environments encountered by facultative intracellular pathogenic bacteria is the intracellular environment of the host cell. Numerous studies have documented that intracellular bacterial pathogens that replicate within phagosomes are simultaneously exposed to multiple signals and they respond to them by a global alteration in protein synthesis that involves elevated levels of several stress-induced proteins. This stress response is manifested regardless of the nature or the stage of maturation of the phagosome of different intracellular pathogens. In contrast, intracellular bacterial pathogens that replicate within the cytoplasm undergo phenotypic modulation in response to the cytoplasmic environment, but their responses do not include elevated levels of stress-induced proteins. This review describes the use of 2-DE to examine bacterial phenotypic modulation in response to the intracellular environment and contrasts this response between three intracellular pathogens; Legionella pneumophila, Salmonella typhimurium, and Listeria monocytogenes. The Legionella pneumophila phagosome is completely blocked from maturation through the endosomal lysosomal pathway but the S. typhimurium phagosome is a specialized compartment that has partial characteristics of an acidified late endosome, while L. monocytogenes rapidly escapes from an acidified phagosome into the cytoplasm.

Animals↗
PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗
PubMedDate not supplied

The role of ATM and ATR in the cellular response to hypoxia and re-oxygenation.

ATM and ATR are stress-response kinases which respond to a variety of insults including ionizing radiation, replication arrest, ultraviolet radiation and hypoxia/re-oxygenation. Hypoxia occupies a unique niche in the study of both ATR- and ATM-mediated checkpoint pathways. Hypoxia is a physiologically significant stress that occurs in virtually all solid tumors and differs from most other stresses in that it does not induce DNA damage. Previous studies have indicated that hypoxia provides a unique way to induce ATR in response to inhibition of DNA replication. During tumor expansion hypoxia is inevitably followed by periods of re-oxygenation which in vitro has been shown to induce significant levels of DNA damage and an ATM response. Therefore both ATR and ATM have a role to play in hypoxia/re-oxygenation.

Animals↗
PubMed1999

The mutagenesis protein UmuC is a DNA polymerase activated by UmuD', RecA, and SSB and is specialized for translesion replication.

Replication of DNA lesions leads to the formation of mutations. In Escherichia coli this process is regulated by the SOS stress response, and requires the mutagenesis proteins UmuC and UmuD'. Analysis of translesion replication using a recently reconstituted in vitro system (Reuven, N. B., Tomer, G., and Livneh, Z. (1998) Mol. Cell 2, 191-199) revealed that lesion bypass occurred with a UmuC fusion protein, UmuD', RecA, and SSB in the absence of added DNA polymerase. Further analysis revealed that UmuC was a DNA polymerase (E. coli DNA polymerase V), with a weak polymerizing activity. Upon addition of UmuD', RecA, and SSB, the UmuC DNA polymerase was greatly activated, and replicated a synthetic abasic site with great efficiency (45% bypass in 6 min), 10-100-fold higher than E. coli DNA polymerases I, II, or III holoenzyme. Analysis of bypass products revealed insertion of primarily dAMP (69%), and to a lesser degree dGMP (31%) opposite the abasic site. The UmuC104 mutant protein was defective both in lesion bypass and in DNA synthesis. These results indicate that UmuC is a UmuD'-, RecA-, and SSB-activated DNA polymerase, which is specialized for lesion bypass. UmuC is a member of a new family of DNA polymerases which are specialized for lesion bypass, and include the yeast RAD30 and the human XP-V genes, encoding DNA polymerase eta.

Bacterial Proteins↗