DNase I behaves as a transcription factor which modulates Fas expression in human cells

Oliveri, Mara; Daga, Antonio; Lunardi, Claudio; Navone, Riccardo; Millo, Romano; Puccetti, Antonio

doi:10.1002/eji.200223817

Cited by 27 publications

(22 citation statements)

References 23 publications

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“…It is not clear, though, whether the DNase I that causes intestinal epithelial apoptosis originated from the same cells (endogenous DNase I) or was internalized from the lumen (exogenous DNase I). Some studies show that DNase I and DNase I-like proteins can be consumed by cells and act as toxins (31, 32). It is likely that internalization of exogenous DNase I was important, because the tips of villi were damaged the most, and the ileum, which is located downstream of the jejunum, was damaged less.…”

Section: Discussionmentioning

confidence: 99%

Deoxyribonuclease I is Essential for DNA Fragmentation Induced by Gamma Radiation in Mice

et al. 2009

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Gamma radiation is known to induce cell death in several organs. This damage is associated with endonuclease-mediated DNA fragmentation; however, the enzyme that produces the latter and is likely to cause cell death is unknown. To determine whether the most abundant cytotoxic endonuclease DNase I mediates γ-radiation-induced tissue injury, we used DNase I knockout mice and zinc chelate of 3,5-diisopropylsalicylic acid (Zn-DIPS), which, as we show, has DNase I inhibiting activity in vitro. The study demonstrated for the first time that inactivation or inhibition of DNase I ameliorates radiation injury to the white pulp of spleen, intestine villi and bone marrow as measured using a quantitative TUNEL assay. The spleen and intestine of DNase I knockout mice were additionally protected from radiation by Zn-DIPS, perhaps due to the broad radioprotective effect of the zinc ions. Surprisingly, the main DNase I-producing tissues such as the salivary glands, pancreas and kidney showed no effect of DNase I inactivation. Another unexpected observation was that even without irradiation, DNA fragmentation and cell death were significantly lower in the intestine of DNase I knockout mice than in wild-type mice. This points to the physiological role of DNase I in normal cell death in the intestinal epithelium. In conclusion, our results suggested that DNase I-mediated mechanism of DNA damage and subsequent tissue injury are essential in γ-radiation-induced cell death in radiosensitive organs.

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Section: Discussionmentioning

confidence: 99%

Deoxyribonuclease I is Essential for DNA Fragmentation Induced by Gamma Radiation in Mice

et al. 2009

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“…DNase I from bovine pancreas was used for in vitro evaluation of enzyme inhibition by spectrophotometric measurement of acid-soluble nucleotides formation at 260 nm (method slightly modified by Bartholeyns et al 40 ). The inhibition was studied in a series of test-tubes with the reaction mixture (total volume 1040 μL), prepared in the following order: (a) test samples contained 80 Kunitz units of DNase I, one of the studied compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) After incubation at 37°C for 30 minutes the reaction was stopped by adding 80 μL of perchloric acid. The percentage of enzyme inhibition was determined by measuring the difference in absorbance that correlates with acid-soluble nucleotides formation; it was calculated as a percentage of specimen absorbance versus absorbance of the solvent control samples.…”

Section: Evaluation Of Dnase I Inhibitionmentioning

confidence: 99%

Benzimidazoles as novel deoxyribonuclease I inhibitors

Kolarević

Ilić

Anastassova

et al. 2018

J of Cellular Biochemistry

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Inhibitory potential of 19 benzimidazoles against bovine pancreatic deoxyribonuclease I (DNase I) was investigated in vitro. Three compounds inhibited DNase I with IC below 100 μM and proved to be more potent DNase I inhibitors than crystal violet (IC = 351.82 ± 29.41 μM), used as a positive control. Compound 9 showed the most potent DNase I inhibition with an IC value of 79.46 ± 11.75 μM. To further explore the relationship between inhibitory activity and 2D pharmacophore features, Pharma/E-State R-group quantitative structure-activity relationship (RQSAR) models were generated and validated using Schrödinger Suite. RQSAR models showed a significant enhancement of benzimidazoles activity using hydrogen-bond acceptor substituents at the R2, R3, and R4 positions, or aryl substituents at the R4 position. The Site Finder module and molecular docking defined the benzimidazoles interactions with the most important catalytic residues of DNase I, including H-acceptor interaction with residue His 134 and His 252 and/or H-donor interaction with residue Glu 39. We also found a positive correlation between IC inhibition values and relative binding free energies of the most active benzimidazoles. In addition, a molecular dynamics simulation was performed for DNase I-compound 9 docking complex in Desmond. Trajectory analysis showed that docking complex and intermolecular interactions were stable throughout the entire production part of simulations. Furthermore, the results of protein structure alignment module suggested the potential translational impact of benzimidazoles against human DNase I. Due to the significant involvement of DNase I in the pathophysiology of many disease conditions, benzimidazoles as DNase I inhibitors could have potential therapeutic applications.

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“…It approximates the size and nuclear diffusion properties of a typical human transcription factor (TF) (1). The enzyme interacts with DNA via the minor groove (2), where it recognizes approximately six consecutive base pairs (3).…”

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confidence: 99%

Probing DNA shape and methylation state on a genomic scale with DNase I

Lazarovici

Zhou

Shafer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

156

187

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DNA binding proteins find their cognate sequences within genomic DNA through recognition of specific chemical and structural features. Here we demonstrate that high-resolution DNase I cleavage profiles can provide detailed information about the shape and chemical modification status of genomic DNA. Analyzing millions of DNA backbone hydrolysis events on naked genomic DNA, we show that the intrinsic rate of cleavage by DNase I closely tracks the width of the minor groove. Integration of these DNase I cleavage data with bisulfite sequencing data for the same cell type's genome reveals that cleavage directly adjacent to cytosine-phosphate-guanine (CpG) dinucleotides is enhanced at least eightfold by cytosine methylation. This phenomenon we show to be attributable to methylationinduced narrowing of the minor groove. Furthermore, we demonstrate that it enables simultaneous mapping of DNase I hypersensitivity and regional DNA methylation levels using dense in vivo cleavage data. Taken together, our results suggest a general mechanism by which CpG methylation can modulate protein-DNA interaction strength via the remodeling of DNA shape.

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DNase I behaves as a transcription factor which modulates Fas expression in human cells

Cited by 27 publications

References 23 publications

Deoxyribonuclease I is Essential for DNA Fragmentation Induced by Gamma Radiation in Mice

Deoxyribonuclease I is Essential for DNA Fragmentation Induced by Gamma Radiation in Mice

Benzimidazoles as novel deoxyribonuclease I inhibitors

Probing DNA shape and methylation state on a genomic scale with DNase I

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