Comparative analysis of epigenetic inhibitors reveals different degrees of interference with transcriptional gene silencing and induction of DNA damage

Q1 · BIOLOGY

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Author: Rozhon, Wilfried ; Tokarz, Barbara ; Pecinka, Ales ; Otmar, Miroslav ; Zwyrtková, Jana ; Dvořák Tomaštíková, Eva ; Procházková, Klára ; Poppenberger, Brigitte ; Nowicka, Anna ; Ercan, Ugur ; Finke, Andreas ; Krečmerová, Marcela ; Schubert, Ingo ; Niezgodzki, Igor

SummaryRepetitive DNA sequences and some genes are epigenetically repressed by transcriptional gene silencing (TGS). When genetic mutants are not available or problematic to use, TGS can be suppressed by chemical inhibitors. However, informed use of epigenetic inhibitors is partially hampered by the absence of any systematic comparison. In addition, there is emerging evidence that epigenetic inhibitors cause genomic instability, but the nature of this damage and its repair remain unclear. To bridge these gaps, we compared the effects of 5‐azacytidine (AC), 2′‐deoxy‐5‐azacytidine (DAC), zebularine and 3‐deazaneplanocin A (DZNep) on TGS and DNA damage repair. The most effective inhibitor of TGS was DAC, followed by DZNep, zebularine and AC. We confirmed that all inhibitors induce DNA damage and suggest that this damage is repaired by multiple pathways with a critical role of homologous recombination and of the SMC5/6 complex. A strong positive link between the degree of cytidine analog‐induced DNA demethylation and the amount of DNA damage suggests that DNA damage is an integral part of cytidine analog‐induced DNA demethylation. This helps us to understand the function of DNA methylation in plants and opens the possibility of using epigenetic inhibitors in biotechnology.

01 Mar 2019·Helvetica Chimica Acta

Label‐Free Quantification of 5‐Azacytidines Directly in the Genome

Author: Stadlmeier, Michael ; Wildenhof, Thomas M. ; Schiffers, Sarah ; Carell, Thomas ; Iwan, Katharina ; Müller, Markus

AbstractAzacytidines (AzaC and AzadC) are clinically relevant pharmaceuticals that operate at the epigenetic level. They are integrated into the genome as antimetabolites to block DNA methylation events. This leads to a reduction of the 5‐methyl‐2′‐deoxycytidine (m5dC) level in the genome, which can activate epigenetically silenced genes. Because of the inherent chemical instability of Aza(d)Cs, their incorporation levels in DNA and RNA are difficult to determine, which hinders correlation of therapeutic effects with incorporation and removal processes. Existing methods involve radioactive labeling and are therefore unsuitable to monitor levels from patients. We report here a new direct chemical method that allows absolute quantification of the levels of incorporated AzaC and AzadC in both RNA and DNA. Furthermore, it clarifies that Aza(d)C accumulates to high levels (up to 12.9 million bases per genome). Although RNA‐based antimetabolites are often 2′‐deoxygenated in vivo and incorporated into DNA, for AzaC we see only limited incorporation into DNA. It accumulates predominantly in RNA where it, however, only leads to insignificant demethylation.

01 Feb 2017·Cytometry Part AQ4 · BIOLOGY

Cell‐based DNA demethylation detection system for screening of epigenetic drugs in 2D, 3D, and xenograft models

Q4 · BIOLOGY

Article

Author: Hajdúch, Marián ; Das, Viswanath ; Agrawal, Khushboo ; Krečmerová, Marcela ; Otmar, Miroslav ; Džubák, Petr

AbstractAberrant DNA methylation that results in silencing of genes has remained a significant interest in cancer research. Despite major advances, the success of epigenetic therapy is elusive due to narrow therapeutic window. A wide variety of naturally occurring epigenetic agents and synthetic molecules that can alter methylation patterns exist, however, their usefulness in epigenetic therapy remains unknown. This underlines the need for effective tumor models for large‐scale screening of drug candidates with potent hypomethylation activity. In this study, we present the development of a cell‐based DNA demethylation detection system, which is amenable for high content screening of epigenetic drugs in two‐dimensional and three‐dimensional cell culture models. Additionally, the detection system also supports the in vivo monitoring of demethylation efficacy of potential lead compounds from in vitro screens in tumor xenografts. The described detection system not only permits the continuous monitoring of demethylation but also of the induced cytostatic/cytotoxic drug effects in live cells, as a function of time. The detection system is fluorescence based and exploits the dominant ability of DNA methylation to inhibit gene transcription, and utilizes FLJ32130 gene, which is silenced on account of promoter hypermethylation in human colorectal cancer. The described work will provide the researchers with an efficient tool for epigenetic drug screens on a high throughput platform and would therefore benefit academic and industrial drug discovery. © 2016 International Society for Advancement of Cytometry

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Phase 2	United States	Koronis Pharmaceuticals, Inc.	01 Jul 2007
HIV Infections	Phase 2	Puerto Rico	Koronis Pharmaceuticals, Inc.	01 Jul 2007

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