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TET-mediated DNA hydroxymethylation is negatively influenced by the PARP-dependent PARylation

Tolic, Anja, Ravichandran, Mirunalini, Rajic, Jovana, Dordevic, Marija, Dordevic, Milos, Dinic, Svetlana, Grdovic, Nevena, Jovanovic, Jelena Arambasic, Mihailovic, Mirjana, Nestorovic, Natasa, Jurkowski, Tomasz P. ORCID: https://orcid.org/0000-0002-2012-0240, Uskokovic, Aleksandra S. and Vidakovic, Melita S. 2022. TET-mediated DNA hydroxymethylation is negatively influenced by the PARP-dependent PARylation. Epigenetics and Chromatin 15 (11) 10.1186/s13072-022-00445-8

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Abstract

Background Poly(ADP-ribosyl)ation (PARylation), a posttranslational modification introduced by PARP-1 and PARP-2, has first been implicated in DNA demethylation due to its role in base excision repair. Recent evidence indicates a direct influence of PARP-dependent PARylation on TET enzymes which catalyse hydroxymethylation of DNA—the first step in DNA demethylation. However, the exact nature of influence that PARylation exerts on TET activity is still ambiguous. In our recent study, we have observed a negative influence of PARP-1 on local TET-mediated DNA demethylation of a single gene and in this study, we further explore PARP–TET interplay. Results Expanding on our previous work, we show that both TET1 and TET2 can be in vitro PARylated by PARP-1 and PARP-2 enzymes and that TET1 PARylation negatively affects the TET1 catalytic activity in vitro. Furthermore, we show that PARylation inhibits TET-mediated DNA demethylation at the global genome level in cellulo. Conclusions According to our findings, PARP inhibition can positively influence TET activity and therefore affect global levels of DNA methylation and hydroxymethylation. This gives a strong rationale for future examination of PARP inhibitors' potential use in the therapy of cancers characterised by loss of 5-hydroxymethylcytosine.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: BioMed Central
ISSN: 1756-8935
Date of First Compliant Deposit: 7 April 2022
Date of Acceptance: 19 March 2022
Last Modified: 10 Nov 2022 11:03
URI: https://orca.cardiff.ac.uk/id/eprint/149106

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