Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation

Simon D. Schwarz, Jianming Xu, Kapila Gunasekera, David Schürmann, Cathrine B. Vågbø, Elena Ferrari, Geir Slupphaug, Michael O. Hottiger, Primo Schär () and Roland Steinacher ()
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Simon D. Schwarz: University of Basel
Jianming Xu: University of Basel
Kapila Gunasekera: University of Zurich
David Schürmann: University of Basel
Cathrine B. Vågbø: Norwegian University of Science and Technology and St. Olavs Hospital
Elena Ferrari: University of Zurich
Geir Slupphaug: Norwegian University of Science and Technology and St. Olavs Hospital
Michael O. Hottiger: University of Zurich
Primo Schär: University of Basel
Roland Steinacher: University of Basel

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The intracellular ATP-ribosyltransferases PARP1 and PARP2, contribute to DNA base excision repair (BER) and DNA demethylation and have been implicated in epigenetic programming in early mammalian development. Recently, proteomic analyses identified BER proteins to be covalently poly-ADP-ribosylated by PARPs. The role of this posttranslational modification in the BER process is unknown. Here, we show that PARP1 senses AP-sites and SSBs generated during TET-TDG mediated active DNA demethylation and covalently attaches PAR to each BER protein engaged. Covalent PARylation dissociates BER proteins from DNA, which accelerates the completion of the repair process. Consistently, inhibition of PARylation in mESC resulted both in reduced locus-specific TET-TDG-targeted DNA demethylation, and in reduced general repair of random DNA damage. Our findings establish a critical function of covalent protein PARylation in coordinating molecular processes associated with dynamic DNA methylation.

Date: 2024
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DOI: 10.1038/s41467-023-44209-8

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