DNA binding properties of minor groove binders and their influence on the topoisomerase II cleavage reaction

Bell, Adam C.; Kittler, L.; Löber, G.; Zimmer, Christoph

doi:10.1002/(sici)1099-1352(199711/12)10:6<245::aid-jmr367>3.0.co;2-3

Cited by 18 publications

(14 citation statements)

References 51 publications

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“…As the two interacting DNA segments in the points of DNA crossovers are repelling, it is tentative to speculate that electrostatic shielding of phosphates by bivalent, symmetrical molecules minimize the repulsion, stabilize the juxtapositions, facilitating the binding of topoisomerases and enhancing in this way their supercoil-relaxing activity. The competition for binding to the same DNA structure can be a limiting factor, however, such interference can be excluded because topoisomerase I (23) and II (24) bind to the minor groove of DNA, whereas spermidine (25) prefers the major groove. In this respect, it is worthwhile to mention that stimulatory effect of vimentin and GFAP on activity of topoisomerases is highly likely mediated via binding of these oligomeric proteins to the points of DNA crossovers (26).…”

Section: Discussionsupporting

confidence: 81%

The caspase-9 derived C-terminal fragment of cytokeratin 18 modulates topoisomerase action

Schütte

Henfling²,

Verheyen³

et al. 2009

Int J Oncol

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Abstract. During early apoptosis the 33 amino acid C-terminal cytokeratin 18 (CK18) fragment is released by caspase-9 cleavage at the 393 DALD/S site. This basic peptide relocates from the cytoskeleton to the nucleoplasm as shown by confocal laser scanning. It is shown that the C-terminal peptide modulates topoisomerase activity as measured by relaxation of plasmid DNA. In an in vitro assay recombinant caspase-induced chromatin condensation is inhibited by the peptide and at the electron microscopical level a clear inhibition of nucleolar breakdown was observed in its presence. We hypothesize that the C-terminal CK18 fragment exerts an effect in the nucleolus by stimulating rRNA transcription and processing via modulation of enzymatic activity of topoisomerase I. This leads to preservation of general transcriptional activity required to exert active steps during early stages of programmed cell death.

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Section: Discussionsupporting

confidence: 81%

The caspase-9 derived C-terminal fragment of cytokeratin 18 modulates topoisomerase action

Schütte

Henfling²,

Verheyen³

et al. 2009

Int J Oncol

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“…To analyze this further, we assembled reconstituted nuclei in vitro in the presence of two sequence-specific antibiotics: 1) Distamycin A, which binds to the minor groove of AT-rich regions of DNA, and 2) Chromomycin A 3, which binds to the minor groove of GC-rich regions of DNA. These two antibiotics have been used previously to define the binding specificities for certain DNA/chromatin-binding proteins, including histone H1 (Kas et al, 1989), topoisomerase II (Bell et al, 1997), and the nuclear envelope protein Lamin B (Rzepecki et al, 1998). Histone H1 and topoisomerase II were prevented from DNA binding by Distamycin A in vitro, whereas in vivo Lamin B was prevented from chromatin binding by Chromomycin A 3 and, to a lesser extent, Distamycin A.…”

Section: The Dominant Negative Fragment Of Elys Does Not Block the Asmentioning

confidence: 84%

Capture of AT-rich Chromatin by ELYS Recruits POM121 and NDC1 to Initiate Nuclear Pore Assembly

Rasala

Ramos

Harel

et al. 2008

MBoC

146

201

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Assembly of the nuclear pore, gateway to the genome, from its component subunits is a complex process. In higher eukaryotes, nuclear pore assembly begins with the binding of ELYS/MEL-28 to chromatin and recruitment of the large critical Nup107-160 pore subunit. The choreography of steps that follow is largely speculative. Here, we set out to molecularly define early steps in nuclear pore assembly, beginning with chromatin binding. Point mutation analysis indicates that pore assembly is exquisitely sensitive to the change of only two amino acids in the AT-hook motif of ELYS. The dependence on AT-rich chromatin for ELYS binding is borne out by the use of two DNA-binding antibiotics. AT-binding Distamycin A largely blocks nuclear pore assembly, whereas GC-binding Chromomycin A 3 does not. Next, we find that recruitment of vesicles containing the key integral membrane pore proteins POM121 and NDC1 to the forming nucleus is dependent on chromatin-bound ELYS/Nup107-160 complex, whereas recruitment of gp210 vesicles is not. Indeed, we reveal an interaction between the cytoplasmic domain of POM121 and the Nup107-160 complex. Our data thus suggest an order for nuclear pore assembly of 1) AT-rich chromatin sites, 2) ELYS, 3) the Nup107-160 complex, and 4) POM121-and NDC1-containing membrane vesicles and/or sheets, followed by (5) assembly of the bulk of the remaining soluble pore subunits. INTRODUCTIONThe possession of a nuclear envelope (NE) that encompasses the genome is the defining characteristic of all eukaryotes. The envelope consists of double nuclear membranes, hundreds to thousands of nuclear pore complexes (NPCs), and in higher eukaryotes, a nuclear lamina. Bidirectional transport of protein and RNA molecules through the nuclear envelope is mediated exclusively by NPCs, large structures ϳ60 -125 MDa in size (Reichelt et al., 1990;Macara, 2001;Quimby and Corbett, 2001;Goldfarb et al., 2004;Pemberton and Paschal, 2005;Patel et al., 2007).In higher eukaryotes the nuclear envelope, including pore complexes, disassembles at mitosis as a prelude to spindle assembly and chromosome segregation (Burke and Ellenberg, 2002;Margalit et al., 2005;Prunuske et al., 2006). This disassembly then necessitates nuclear envelope reformation around each set of segregated chromosomes toward the end of mitosis, a process that involves both nuclear membrane recruitment and nuclear pore formation.Analysis of the pore subunits produced by mitotic disassembly has provided the most useful clues to nearest neighbor interactions within the vertebrate pore. Vertebrate nuclear pores are comprised of ϳ30 different proteins or nucleoporins (Nups) in 8-32 copies each, to give a 500-1000 protein structure (Cronshaw et al., 2002). At mitosis the massive vertebrate pore disassembles into ϳ14 soluble subunits, each with a distinct protein composition, whereas the integral membrane pore proteins, POM121, NDC1, and gp210, segregate into endoplasmic reticulum (ER) sheets and vesicles (Gerace et al., 1982;Wozniak et al., 1989;Greber et al., 1990;Hallberg ...

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“…1 and 2). Dist A is a member of a class of drugs termed minor-groove binders whose hallmark is sequence-and conformation-specific binding to AT-rich sequences in the minor groove of DNA (34). We have previously used Dist A in vitro to inhibit binding of high mobility group I/Y (17,35,36), which is one of a select group of architectural transcription factors that binds exclusively to the minor groove of DNA (37).…”

Section: Discussionmentioning

confidence: 99%

Reduction of Nitric Oxide Synthase 2 Expression by Distamycin A Improves Survival from Endotoxemia

Baron

Carvajal

Liu

et al. 2004

The Journal of Immunology

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NO synthase 2 (NOS2) plays an important role in endotoxemia through overproduction of NO. Distamycin A (Dist A) belongs to a class of drugs termed minor-groove DNA binders, which can inhibit transcription factor binding to AT-rich regions of DNA. We and others have previously shown that AT-rich regions of DNA surrounding transcription factor binding sites in the NOS2 promoter are critical for NOS2 induction by inflammatory stimuli in vitro. Therefore, we hypothesized that Dist A would attenuate NOS2 up-regulation in vivo during endotoxemia and improve animal survival. C57BL/6 wild-type (WT) mice treated with Dist A and LPS (endotoxin) showed significantly improved survival compared with animals treated with LPS alone. In contrast, LPS-treated C57BL/6 NOS2-deficient (NOS2−/−) mice did not benefit from the protective effect of Dist A on mortality from endotoxemia. Treatment with Dist A resulted in protection from hypotension in LPS-treated WT mice, but not in NOS2−/− mice. Furthermore, LPS-induced NOS2 expression was attenuated in vivo (WT murine tissues) and in vitro (primary peritoneal and RAW 264.7 murine macrophages) with addition of Dist A. Dist A selectively decreased IFN regulatory factor-1 DNA binding in the enhancer region of the NOS2 promoter, and this IFN regulatory factor-1 site is critical for the effect of Dist A in attenuating LPS induction of NOS2. Our data point to a novel approach in modulating NOS2 expression in vivo during endotoxemia and suggest the potential for alternative treatment approaches for critical illness.

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DNA binding properties of minor groove binders and their influence on the topoisomerase II cleavage reaction

Cited by 18 publications

References 51 publications

The caspase-9 derived C-terminal fragment of cytokeratin 18 modulates topoisomerase action

The caspase-9 derived C-terminal fragment of cytokeratin 18 modulates topoisomerase action

Capture of AT-rich Chromatin by ELYS Recruits POM121 and NDC1 to Initiate Nuclear Pore Assembly

Reduction of Nitric Oxide Synthase 2 Expression by Distamycin A Improves Survival from Endotoxemia

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