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

0531220 - ÚEB 2021 RIV GB eng J - Journal Article
Nowicka, Anna - Tokarz, Barbara - Zwyrtková, Jana - Tomaštíková, Eva - Procházková, Klára - Ercan, U. - Finke, A. - Rozhon, W. - Poppenberger, B. - Otmar, M. - Niezgodzki, I. - Krečmerová, Marcela - Schubert, I. - Pečinka, Aleš
Comparative analysis of epigenetic inhibitors reveals different degrees of interference with transcriptional gene silencing and induction of DNA damage.
Plant Journal. Roč. 102, č. 1 (2020), s. 68-84. ISSN 0960-7412. E-ISSN 1365-313X
R&D Projects: GA MŠMT(CZ) EF16_019/0000827; GA MŠMT(CZ) LTC18026; GA ČR(CZ) GA19-13848S
Grant - others:AVČR(CZ) Purkyně Fellowship
Institutional support: RVO:61389030 ; RVO:61388963
Keywords : Arabidopsis thaliana * cytidine analog * DNA damage * DNA methylation * epigenetic inhibitors * genome stability * Vicia faba
OECD category: Biochemistry and molecular biology
Impact factor: 6.486, year: 2020
Method of publishing: Open access
http://doi.org/10.1111/tpj.14612

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), 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.
Permanent Link: http://hdl.handle.net/11104/0309933