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

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

Abstract

Repetitive 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), 20-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.
Author Anna Nowicka - The Czech Academy of Sciences
Anna Nowicka,,
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, Barbara Tokarz (FoBaH / Department of Botany, Physiology and Plant Protection)
Barbara Tokarz,,
- Department of Botany, Physiology and Plant Protection
, Jana Zwyrtková - The Czech Academy of Sciences
Jana Zwyrtková,,
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, Eva Dvořák Tomaštíková - The Czech Academy of Sciences
Eva Dvořák Tomaštíková,,
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, Klára Procházková - The Czech Academy of Sciences
Klára Procházková,,
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, Ugur Ercan - Max Planck Institute for Plant Breeding Research (MPIPZ)
Ugur Ercan,,
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, Andreas Finke - Max Planck Institute for Plant Breeding Research (MPIPZ)
Andreas Finke,,
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, Wilfried Rozhon - Technical University of Munich
Wilfried Rozhon,,
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, Brigitte Poppenberger - Technical University of Munich
Brigitte Poppenberger,,
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, Miroslav Otmar - Institute of Organic Chemistry and Biochemistry AS CR
Miroslav Otmar,,
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et al.`
Journal seriesPlant Journal, ISSN 0960-7412, e-ISSN 1365-313X, (N/A 140 pkt)
Issue year2020
Vol102
No1
Pages68-84
Publication size in sheets0.3
Keywords in English DNA methylation, genome stability, DNA damage, cytidine analog, epigenetic inhibitors, Arabidopsis thaliana, Vicia faba
ASJC Classification1110 Plant Science; 1307 Cell Biology; 1311 Genetics
DOIDOI:10.1111/tpj.14612
URL https://onlinelibrary.wiley.com/doi/abs/10.1111/tpj.14612
Languageen angielski
Score (nominal)140
Score sourcejournalList
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2017 = 1.669; WoS Impact Factor: 2018 = 5.726 (2) - 2018=6.467 (5)
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