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1.
Bernd Kaina Geoffrey P. Margison Markus Christmann 《Cellular and molecular life sciences : CMLS》2010,67(21):3663-3681
O
6-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O
6-methylguanine and O
6-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic,
and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued.
A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O
6-benzylguanine and O
6-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate
MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This
might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated
that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise
for enhancing the effectiveness of alkylating agent chemotherapy. 相似文献
2.
Bolin C Boudra MT Fernet M Vaslin L Pennaneach V Zaremba T Biard D Cordelières FP Favaudon V Mégnin-Chanet F Hall J 《Cellular and molecular life sciences : CMLS》2012,69(6):951-962
Cyclin-dependent kinase 5 (Cdk5) has been identified as a determinant of sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Here, the consequences of its depletion on cell survival, PARP activity, the recruitment of base excision repair (BER) proteins to DNA damage sites, and overall DNA single-strand break (SSB) repair were investigated using isogenic HeLa stably depleted (KD) and Control cell lines. Synthetic lethality achieved by disrupting PARP activity in Cdk5-deficient cells was confirmed, and the Cdk5KD cells were also found to be sensitive to the killing effects of ionizing radiation (IR) but not methyl methanesulfonate or neocarzinostatin. The recruitment profiles of GFP-PARP-1 and XRCC1-YFP to sites of micro-irradiated Cdk5KD cells were slower and reached lower maximum values, while the profile of GFP-PCNA recruitment was faster and attained higher maximum values compared to Control cells. Higher basal, IR, and hydrogen peroxide-induced polymer levels were observed in Cdk5KD compared to Control cells. Recruitment of GFP-PARP-1 in which serines 782, 785, and 786, potential Cdk5 phosphorylation targets, were mutated to alanines in micro-irradiated Control cells was also reduced. We hypothesize that Cdk5-dependent PARP-1 phosphorylation on one or more of these serines results in an attenuation of its ribosylating activity facilitating persistence at DNA damage sites. Despite these deficiencies, Cdk5KD cells are able to effectively repair SSBs probably via the long patch BER pathway, suggesting that the enhanced radiation sensitivity of Cdk5KD cells is due to a role of Cdk5 in other pathways or the altered polymer levels. 相似文献
3.
Double-strand breaks (DSBs) are the most detrimental form of DNA damage. Failure to repair these cytotoxic lesions can result
in genome rearrangements conducive to the development of many diseases, including cancer. The DNA damage response (DDR) ensures
the rapid detection and repair of DSBs in order to maintain genome integrity. Central to the DDR are the DNA damage checkpoints.
When activated by DNA damage, these sophisticated surveillance mechanisms induce transient cell cycle arrests, allowing sufficient
time for DNA repair. Since the term “checkpoint” was coined over 20 years ago, our understanding of the molecular mechanisms
governing the DNA damage checkpoint has advanced significantly. These pathways are highly conserved from yeast to humans.
Thus, significant findings in yeast may be extrapolated to vertebrates, greatly facilitating the molecular dissection of these
complex regulatory networks. This review focuses on the cellular response to DSBs in Saccharomyces cerevisiae, providing a comprehensive overview of how these signalling pathways function to orchestrate the cellular response to DNA
damage and preserve genome stability in eukaryotic cells. 相似文献
4.
Summary In vitro exposure of guinea-pig pancreatic slices to NMUT resulted in an increase in hydroxyurea-insensitive3H-TdR incorporation into DNA; this represents DNA repair synthesis following NMUT-induced DNA damage. The kinetics of this hydroxyurea-insensitive3H-TdR incorporation suggest that the NMUT-induced DNA damage is largely repaired within 2 hours.Environmental Health Programs, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 (USA). These studies were supported by National Cancer Institute (Bethesda, Md., USA). Contract No. N01-CP-23284. Technical assistance of MS.Mary Majdan is gratefully acknowledged. 相似文献
5.
Summary The catalysis of H2O2 decomposition by Cu2+-complexes of RNA and DNA has been investigated. It is shown that both complexes decompose H2O2, but only the Cu2+-RNA-system shows peroxidative activity too, e.g. only in this case the nucleotide bases are degraded. Thermal denaturation of DNA also leads to a Cu2+-complex with peroxidative activity, the latter being dependent on the degree of denaturation.
V. Mitteilung:S. Petri, H. Sigel undH. Erlenmeyer, Helv. chim. Acta49, 1778 (1966).
12. Mitteilung überMetallionen und H 2 O 2; 11. Mitteilung:H. Ch. Curtius, P. Anders, R. Zell, H. Sigel undH. Erlenmeyer, Helv. chim. Acta49, 2256 (1966). 相似文献
V. Mitteilung:S. Petri, H. Sigel undH. Erlenmeyer, Helv. chim. Acta49, 1778 (1966).
12. Mitteilung überMetallionen und H 2 O 2; 11. Mitteilung:H. Ch. Curtius, P. Anders, R. Zell, H. Sigel undH. Erlenmeyer, Helv. chim. Acta49, 2256 (1966). 相似文献
6.
Le Bouffant R Cormier P Cueff A Bellé R Mulner-Lorillon O 《Cellular and molecular life sciences : CMLS》2007,64(13):1723-1734
DNA integrity checkpoint control was studied in the sea urchin early embryo. Treatment of the embryos with genotoxic agents
such as methyl methanesulfonate (MMS) or bleomycin induced the activation of a cell cycle checkpoint as evidenced by the occurrence
of a delay or an arrest in the division of the embryos and an inhibition of CDK1/cyclin B activating dephosphorylation. The
genotoxic treatment was shown to induce DNA damage that depended on the genotoxic concentration and was correlated with the
observed cell cycle delay. At low genotoxic concentrations, embryos were able to repair the DNA damage and recover from checkpoint
arrest, whereas at high doses they underwent morphological and biochemical changes characteristic of apoptosis. Finally, extracts
prepared from embryos were found to be capable of supporting DNA repair in vitro upon incubation with oligonucleotides mimicking damage. Taken together, our results demonstrate that sea urchin early embryos
contain fully functional and activatable DNA damage checkpoints. Sea urchin embryos are discussed as a promising model to
study the signaling pathways of cell cycle checkpoint, DNA repair and apoptosis, which upon deregulation play a significant
role in the origin of cancer.
Received 10 April 2007; accepted 23 April 2007 相似文献
7.
Summary Host cell reactivation capacity for ozone T3 phage was determined for differentE. coli strains deficient in one or more of the DNA repair mechanisms. The results indicate that DNA polymerase I appears to play a key role in the repair of damage produced on the DNA by ozone while thelexA gene product seems to play a minor one.This research was sponsored by the National Sciences and Engineering Council of Canada. One of us (PLH) acknowledges a scholarship from the NSERCof Canada. 相似文献
8.
S. Kjellev 《Cellular and molecular life sciences : CMLS》2009,66(8):1350-1369
The trefoil factor family (TFF) comprises a group of small peptides which are highly expressed in tissues containing mucus-producing
cells – especially in the mucosa lining the gastrointestinal tract. The peptides seem crucial for epithelial restitution and
may work via other pathways than the conventional factors involved in restitution. In vitro studies have shown that the TFFs promote restitution using multiple mechanisms. The peptides also have other functionalities
including interactions with the immune system. Moreover, therapeutic effects of the TFFs have been shown in several animal
models of gastrointestinal damage. Still it is not clear which of their in vitro properties are involved in the in vivo mode of action. This review describes the TFF family with emphasis on their biological properties and involvement in mucosal
protection and repair.
Received 10 October 2008; received after revision 07 November 2008; accepted 10 November 2008 相似文献
9.
Antoni Camins Javier G. Pizarro Daniel Alvira Javier Gutierrez-Cuesta Aurelio Vazquez de la Torre Jaume Folch Francesc X. Sureda Ester Verdaguer Felix Junyent Joaquín Jordán Isidre Ferrer Mercè Pallàs 《Cellular and molecular life sciences : CMLS》2010,67(22):3865-3882
In the present study we demonstrated that neurotoxin MPP+-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP+-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson’s disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G0/G1 cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP+ leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP+ and cell-cycle re-entry through retinoblastoma protein phosphorylation. 相似文献
10.
M. Mathy-Hartert G. Deby-Dupont P. Melin M. Lamy C. Deby 《Cellular and molecular life sciences : CMLS》1996,52(2):167-174
Myeloperoxidase (MPO) is an enzyme located within polymorphonuclear neutrophils capable of producting cytotoxic oxidant species that are particularly active against bacteria with polysaccharide capsules.Pseudomonas aeruginosa (106 bacteria per 1 ml) are killed within 1 h in vitro by a MPO/H2O2/Cl– system (48 mU=132 ng of MPO). The question arose as to whether human macrophages would acquire cytotoxic activity when loaded with this enzyme. Monocytes were therefore isolated from human blood and cultured for up to ten days to induce maturation to macrophages. These cells lost endogenous MPO within five days while H2O2 production in response to stimulation by phorbol myristate acetate (10–6M) decreased to 23% within ten days. On the other hand, their capacity to take up exogenous MPO increased fourfold from day three to day ten. Human macrophages cultured from eight days (when both H2O2 production and MPO uptake were sufficient) were therefore used to study the effects of MPO uptake on cytocidal activity againstPseudomonas aeruginosa. After a 1 h MPO loading period, macrophages (5×105 cells per ml) were incubated in the presence of bacteria (0.5 to 2×106 bacteria per ml) for 2 h at 37°C. At a bacteria/macrophage ratio of 1, only 34.8±7.0% of bacteria survived (compared to killing by non-loaded macrophages), while 74.4±9.3% survived at a ratio of 4. From these results, we conclude that loading macrophages with exogenous MPO could enhance their microbicidal activity, suggesting a potentially useful therapeutic application. 相似文献
11.
Base excision DNA repair 总被引:2,自引:0,他引:2
Zharkov DO 《Cellular and molecular life sciences : CMLS》2008,65(10):1544-1565
DNA repair is a collection of several multienzyme, multistep processes keeping the cellular genome intact against genotoxic insults. One of these processes is base excision repair, which deals with the most ubiquitous lesions in DNA: oxidative base damage, alkylation, deamination, sites of base loss and single-strand breaks, etc. Individual enzymes acting in base excision repair have been identified. The recent years were marked with many advances in understanding of their structure and many interactions that make base excision repair a functional, versatile system. This review describes the current knowledge of structural biology and biochemistry of individual steps of base excision repair, several subpathways of the common base excision repair pathway, and interactions of the repair process with other cellular processes. 相似文献
12.
13.
14.
Kinetics of BRCA1 regulation in response to UVC radiation 总被引:1,自引:0,他引:1
To investigate changes in BRCA1 following DNA damage, we exposed MCF-7 cells to increasing doses of ultraviolet C. We observed
an increase in BRCA1 protein levels above 78 J/m2. This increase was observed as early as 5 min after irradiation. BRCA1 levels were then observed to decrease after 2 h, consistent
with the previously published data. By pretreating with cycloheximide prior to irradiation, we observed a decrease in the
protein half-life, from 3.5 h to 53 min, suggesting that a decrease in protein half-life may cause the lower levels of BRCA1
after irradiation. We also observed an increase in BRCA1 mRNA within 15 min of irradiation, followed by a decrease after 4
h. These data suggest that newly translated protein may contribute to increases in BRCA1 protein levels. The very rapid changes
in BRCA1 support its role as a sensor of DNA damage, as opposed to being a repair gene.
Received 6 April 2000; received after revision 23 May 2000; accepted 23 May 2000 相似文献
15.
In plants three different approaches have been used to study homologous DNA recombination; extrachromosomal recombination (ECR) between transfected DNA molecules, intrachromosomal recombination (ICR) between repeated genes integrated into and resident at the genome and recombination between introduced DNA and homologous sequences in the genome (gene targeting). ECR is efficient (10–1 to 10–3) and occurs mainly during a limited time period early after transfection. It proceeds predominantly via nonconservative single-strand annealing. ICR, which in most cases is described best by the double-strand break repair model of recombination, occurs at frequencies of one event in 105 to 107 cells. ICR takes place throughout the whole life-cycle of a plant, in all organs and at different developmental stages. As there exists no predetermined germline in plants, somatic recombination events can be transferred to the next generation. Recombination frequencies are enhanced by DNA damage. Gene targeting, like ICR, occurs at low rates in plant cells. Almost nothing is known about the enzymes involved in homologous recombination in plants. 相似文献
16.
17.
The superoxide-generating NADPH oxidase: structural aspects and activation mechanism 总被引:31,自引:0,他引:31
Vignais PV 《Cellular and molecular life sciences : CMLS》2002,59(9):1428-1459
Flavocytochrome b
558
is the catalytic core of the respiratory-burst oxidase, an enzyme complex that catalyzes the NADPH-dependent reduction of
O2 into the superoxide anion O2
- in phagocytic cells. Flavocytochrome b
558
is anchored in the plasma membrane. It is a heterodimer that consists of a large glycoprotein gp91phox (phox for phagocyte oxidase) (β subunit) and a small protein p22phox (α subunit). The other components of the respiratory-burst oxidase are water-soluble
proteins of cytosolic origin, namely p67phox, p47phox, p40phox and Rac. Upon cell stimulation, they assemble with the membrane-bound
flavocytochrome b
558
which becomes activated and generates O2
-. A defect in any of the genes encoding gp91phox, p22phox, p67phox or p47phox results in chronic granulomatous disease, a
genetic disorder characterized by severe and recurrent infections, illustrating the role of O2
- and the derived metabolites H2O2 and HOCl in host defense against invading microorganisms. The electron carriers, FAD and hemes b, and the binding site for NADPH are confined to the gp91phox subunit of flavocytochrome b
558
. The p22phox subunit serves as a docking site for the cytosolic phox proteins. This review provides an overview of current
knowledge on the structural organization of the O2
--generating flavocytochrome b
558
, its kinetics, its mechanism of activation and the regulation of its biosynthesis. Homologues of gp91phox, called Nox and
Duox, are present in a large variety of non-phagocytic cells. They exhibit modest O2
--generating oxidase activity, and some act as proton channels. Their role in various aspects of signal transduction is currently
under investigation and is briefly discussed.
Received 28 May 2002; received after revision 20 June 2002; accepted 24 June 2002 相似文献
18.
Nick Fulcher Elisa Derboven Sona Valuchova Karel Riha 《Cellular and molecular life sciences : CMLS》2014,71(5):847-865
Genome organization into linear chromosomes likely represents an important evolutionary innovation that has permitted the development of the sexual life cycle; this process has consequently advanced nuclear expansion and increased complexity of eukaryotic genomes. Chromosome linearity, however, poses a major challenge to the internal cellular machinery. The need to efficiently recognize and repair DNA double-strand breaks that occur as a consequence of DNA damage presents a constant threat to native chromosome ends known as telomeres. In this review, we present a comparative survey of various solutions to the end protection problem, maintaining an emphasis on DNA structure. This begins with telomeric structures derived from a subset of prokaryotes, mitochondria, and viruses, and will progress into the typical telomere structure exhibited by higher organisms containing TTAGG-like tandem sequences. We next examine non-canonical telomeres from Drosophila melanogaster, which comprise arrays of retrotransposons. Finally, we discuss telomeric structures in evolution and possible switches between canonical and non-canonical solutions to chromosome end protection. 相似文献
19.
Summary In tumour and normal rat tissues prolonged alkylation of DNA and RNA by chlorambucil-3H occurs over periods of 24 h. It is suggested that this may indicate the slow release of an alkylating moiety from an intracellular drugmacromolecule complex. 相似文献
20.
Summary
Streptomyces species 3M grew in peptone yeast extract medium with 1000 g/ml K2Cr2O7. Incubation of the chromate with different cell fractions in the presence of NADH and NADPH resulted in a decrease of Cr6+ in the reaction mixture. The level of Cr6+ was reduced by 82.7% by a particulate cell fraction obtained by centrifugation at 105,000×g for 1 h, in the presence of NADH. The reducing enzyme was associated with this cell fraction. The enzyme was constitutive and reduced Cr6+ to Cr3+. 相似文献