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41.
Biophysics - Abstract—The absorption spectra of lysed and non-lysed erythrocyte samples isolated from chicken, goose, and guinea pig blood were studied. It was found that the position of the... 相似文献
42.
In this report we show that human DNA Topoisomerase I (Top1) forms DNA-protein adducts with nicked and gapped DNA structures lacking a conventional Top1 cleavage site. The radioactively labeled crosslinking products were identified by SDS-gel electrophoresis. The chemical structure of the groups at 5' or 3' end of the nick does not have an effect on the formation of these covalent adducts. Therefore, all kinds of nicks, either directly induced by ionizing radiation or reactive oxygen species or indirectly induced in the course of base excision repair (BER) are targets for Top1 that competes with BER proteins and other nick-sensors. Top1-DNA covalent adducts formed in cells exposed to DNA damaging agents can promote genetic instability. 相似文献
43.
Julia C. Hoffmann Alexander Pappa Peter H. Krammer Inna N. Lavrik 《Molecular and cellular biology》2009,29(16):4431-4440
Caspase-8 is the main initiator caspase in death receptor-induced apoptosis. Procaspase-8 is activated at the death-inducing signaling complex (DISC). Previous studies suggested a two-step model of procaspase-8 activation. The first cleavage step occurs between the protease domains p18 and p10. The second cleavage step takes place between the prodomain and the large protease subunit (p18). Subsequently, the active caspase-8 heterotetramer p182-p102 is released into the cytosol, starting the apoptotic signaling cascade. In this report, we have further analyzed procaspase-8 processing upon death receptor stimulation directly at the DISC and in the cytosol. We have found an alternative sequence of cleavage events for procaspase-8. We have demonstrated that the first cleavage can also occur between the prodomain and the large protease subunit (p18). The resulting cleavage product, p30, contains both the large protease subunit (p18) and the small protease subunit (p10). p30 is further processed to p10 and p18 by active caspases. Furthermore, we show that p30 can sensitize cells toward death receptor-induced apoptosis. Taken together, our data suggest an alternative mechanism of procaspase-8 activation at the DISC.Apoptosis can be triggered by a number of factors, including UV or γ-irradiation, chemotherapeutic drugs, and signaling from death receptors (11, 12). CD95 (APO-1/Fas) is a member of the death receptor family, a subfamily of the tumor necrosis factor receptor (TNF-R) superfamily (1, 30). Eight members of the death receptor subfamily have been characterized so far: TNF-R1 (DR1, CD120a, p55, p60), CD95 (DR2, APO-1, Fas), DR3 (APO-3, LARD, TRAMP, WSL1), TRAIL-R1 (APO-2, DR4), TRAIL-R2 (DR5, KILLER, TRICK2), DR6, EDA-R, and NGF-R (13). Cross-linking of CD95 by its natural ligand, CD95L (CD178) (29), or by agonistic antibodies induces apoptosis in sensitive cells (31, 36). The death-inducing signaling complex (DISC) is formed within seconds after CD95 stimulation (9). The DISC consists of oligomerized, probably trimerized CD95 receptors, the adaptor molecule FADD, two isoforms of procaspase-8 (procaspase-8a and -8b), procaspase-10, and c-FLIPL/S/R (6, 19, 21, 25, 27). The interactions between molecules at the DISC are based on homotypic contacts. The death domain of the receptor interacts with the death domain of FADD, while the death effector domain (DED) of FADD interacts with the N-terminal tandem DEDs of procaspase-8 and -10 and c-FLIPL/S/R.Two isoforms of procaspase-8 (procaspase-8a and procaspase-8b) were reported to be bound to the DISC (24). Both isoforms possess two tandem DEDs, as well as the catalytic subunits p18 and p10 (see Fig. Fig.1A).1A). Procaspase-8a contains an additional 2-kDa (15-amino-acid [aa]) fragment, which results from the translation of exon 9. This small fragment is located between the second DED and the large catalytic subunit, resulting in different lengths of procaspase-8a and -8b (p55 and p53 kDa), respectively.Open in a separate windowFIG. 1.A new 30-kDa protein is detected by the anti-caspase-8 MAb C15. (A) Scheme of procaspase-8 and its cleavage products. The binding sites of the anti-caspase-8 MAbs C5 and C15 are indicated. (B) The B-lymphoblastoid cell lines SKW6.4, Raji, and BJAB and the T-cell lines CEM, Jurkat 16, and caspase-8-deficient Jurkat (clone JI9.2) were stimulated with LZ-CD95L for the indicated times, followed by caspase-8 immunoprecipitation (C8-IP) using the anti-caspase-8 MAb C15 directed against the p18 subunit of procaspase-8. Western blotting of immunoprecipitates was performed using the anti-caspase-8 MAb C15 (**, Ig heavy chain; *, unspecific band). (C) SKW6.4 cells were stimulated with LZ-CD95L for different times, and procaspase-8 processing in total cellular lysates was analyzed by Western blotting using the anti-caspase-8 MAb C15. (D) B-lymphoblastoid BJAB cells were stimulated with LZ-TRAIL for different times, and procaspase-8 processing was analyzed as described for panel C. (E) Primary human T cells (day 6) were stimulated with LZ-CD95L, and procaspase-8 processing was analyzed as described for panel C (*, unspecific band).Activation of procaspase-8 is believed to follow an “induced-proximity” model in which high local concentrations and a favorable mutual orientation of procaspase-8 molecules at the DISC lead to their autoproteolytic processing (2, 3, 20). There is strong evidence from several in vitro studies that autoproteolytic activation of procaspase-8 occurs after oligomerization at the receptor complex (20). Furthermore, it has been shown that homodimers of procaspase-8 have proteolytic activity and that proteolytic processing of procaspase-8 occurs between precursor homodimers (3).Procaspase-8a/b (p55/p53) processing at the DISC has been described to involve two sequential cleavage steps (see Fig. Fig.1A).1A). This process is referred to as the “two-step model” (3, 17). The first cleavage step occurs between the two protease domains, and the second cleavage step takes place between the prodomain and the large protease subunit (see Fig. Fig.1A)1A) (15). During the first cleavage step, the cleavage at Asp374 generates the two subunits p43/p41 and p12. Both cleavage products remain bound to the DISC: p43/p41 by DED interactions and p12 by interactions with the large protease domain of p43/p41. The second cleavage step takes place at Asp216 and Asp384, producing the active enzyme subunits p18, p10, and the prodomain p26/p24. As a result of procaspase-8 processing, the active caspase-8 heterotetramer p182-p102 is formed at the DISC. This heterotetramer is subsequently released into the cytosol, starting the apoptotic signaling cascade (14).Recent studies have shown that processing of procaspase-8 at the DISC is more complicated and can involve additional steps like the generation of a prolonged prodomain of procaspase-8, termed CAP3 (p27), that is quickly converted to p26 (see Fig. Fig.1A)1A) (7).In addition to its central role in death receptor-induced apoptosis, caspase-8 was reported to be required for proliferation of lymphocytes (12, 23). Recently caspase-8 was shown to be an important factor for NF-κB activation following T-cell receptor stimulation (28). The mechanism underlying the dual role of caspase-8 activity and its regulation is largely unknown.In the present study, we show that upon death receptor stimulation, p30 is formed by cleavage at Asp210, a yet-unknown cleavage product of procaspase-8, which comprises the C terminus of procaspase-8. p30 turned out to be a key intermediate product in the course of procaspase-8 processing. Furthermore, we suggest that the p30-mediated activation of procaspase-8 plays an important role in the amplification of the death signal. Taken together, our findings provide a new mechanism of procaspase-8 activation and extend the current two-step cleavage model by an alternative activation pathway. 相似文献
44.
N. A. Lebedeva N. I. Rechkunova K. Agama Y. Pommier O. I. Lavrik 《Biochemistry. Biokhimii?a》2009,74(11):1278-1284
The interaction of human recombinant DNA topoisomerase 1 (Top1) with linear and circular DNA structures containing a nick
or short gap but lacking a specific Top1 recognition site was studied. The effect of key excision repair proteins on formation
of the Top1 covalent adduct with the DNA repair intermediates was shown. Partial inhibition of the Top1-DNA-adduct formation
upon addition of poly(ADP-ribose) polymerase 1 in the absence of NAD+ was shown, whereas in the presence of NAD+ formation of a high molecular weight product, most likely corresponding to poly(ADP)-ribosylated Top1-DNA adduct, was observed.
The data show that the key base excision repair proteins can influence formation of suicide Top1-DNA adducts. Top1 was identified
by immunoprecipitation in the bovine testis nuclear extract as the protein forming the main modification product with nick-containing
DNA. 相似文献
45.
Kutuzov MM Ilina ES Sukhanova MV Pyshnaya IA Pyshnyi DV Lavrik OI Khodyreva SN 《Biochemistry. Biokhimii?a》2011,76(1):147-156
To study the interaction of poly(ADP-ribose) polymerase 1 (PARP1) with apurinic/apyrimidinic sites (AP sites) within clustered
damages, DNA duplexes were created that contained an AP site in one strand and one of its analogs situated opposite the AP
site in the complementary strand. Residues of 3-hydroxy-2-hydroxymethyltetrahydrofuran (THF), diethylene glycol (DEG), and
decane-1,10-diol (DD) were used. It is shown for the first time that apurinic/apyrimidinic endonuclease 1 (APE1) cleaves the
DNA strands at the positions of DEG and DD residues, and this suggests these groups as AP site analogs. Insertion of DEG and
DD residues opposite an AP site decreased the rate of AP site hydrolysis by APE1 similarly to the effect of the THF residue,
which is a well-known analog of the AP site, and this allowed us to use such AP DNAs to imitate DNA with particular types
of clustered damages. PARP1, isolated and in cell extracts, efficiently interacted with AP DNA with analogs of AP sites producing
a Schiff base. PARP1 competes with APE1 upon interaction with AP DNAs, decreasing the level of its cross-linking with AP DNA,
and inhibits hydrolysis of AP sites within AP DNAs containing DEG and THF residues. Using glutaraldehyde as a linking agent,
APE1 is shown to considerably decrease the amount of AP DNA-bound PARP1 dimer, which is the catalytically active form of this
enzyme. Autopoly(ADP-ribosyl)ation of PARP1 decreased its inhibitory effect. The possible involvement of PARP1 and its automodification
in the regulation of AP site processing within particular clustered damages is discussed. 相似文献
46.
Zakharenko AL Sukhanova MV Khodyreva SN Novikov FN Stroĭlov VS Nilov DK Chilov GG Shviadas VK Lavrik OI 《Molekuliarnaia biologiia》2011,45(3):565-569
A search for poly(ADP-ribose) polymerase-1 inhibitors by virtual screening of a chemical compound database and a subsequent experimental verification of their activities have been done. It was shown that the most efficient method to predict inhibitory properties implies a combinatorial approach joining molecular docking capabilities with structural filtration. Among more than 300000 database chemicals 9 PARP1 inhibitors were revealed; the most active ones, namely: STK031481, STK056130, and STK265022,--displayed biological effect at a micro-molar concentration (IC50 = 2.0 microM, 1.0 microM and 2.6 microM, respectively). 相似文献
47.
The activities of green cell-free extracts of spinach leavesin performing photochemical transphosphorylation, photosyntheticphosphorylation, the HILL reaction and the light-induced formationof the endogenous reducing substance (ascorbic acid) were followedin parallel during the growth process of the plant. There wasa certain parallelism between the development of the activitiesof photochemical transphosphorylation, of photo-synthetic phosphorylationand of the HILL reaction, activities being low in the earlierstage of growth, reaching a maximum just before efflorescence,and showing thereafter a more or less sharp decline. The activityin the light-induced formation of endogenous reducing substancewas undetectable for the first 35 day-period of growth, reacheda maximum about one week earlier than the other three activities,and again disappeared after 60 days of growth. (Received September 9, 1960; ) 相似文献
48.
The influence of the drug Actovegin on the proliferative activity and mitotic regime of cells of transplanted RK-15-1EKVM and VNK-21 clone 13/04 lines is studied. The stimulating effect of the drug on cell proliferation when added to a growth medium containing cattle blood serum of differing compositions and at different concentrations is demonstrated. It is concluded that Actovegin shows promise for use in bioengineering of cell cultures. 相似文献
49.
50.
It has been shown that, in the absence of dATP in the poly(dT).oligo(dA) template-primer complex, the rate of primer cleavage by the E. coli DNA polymerase I Klenow fragment equals 4% of polymerization rate, while in the presence of dATP it equals as much as 50-60%. NaF and NMP taken separately inhibit exonuclease cleavage of oligo(dA) both with and without dATP. The addition of NaF (5-10 mM) or NMP (5-20 mM) increases the absolute increment of polymerization rate 5-9-fold relative to the absolute decrement of the rate of nuclease hydrolysis of primer. This proves the assumption that not more than 10-20% of primer molecules, interacting with the exonuclease center of polymerase, are cleaved by the enzyme. Presumably, NaF and nucleotides disturb the coupling of the 3'-end of oligonucleotide primer to the exonuclease center of the enzyme. As the primers mostly form complexes with the polymerizing center, the reaction of polymerization is activated. 相似文献