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Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation

Author

Listed:
  • Simon D. Schwarz

    (University of Basel)

  • Jianming Xu

    (University of Basel
    University of Zurich)

  • Kapila Gunasekera

    (University of Zurich
    University of Bern)

  • 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
    ETH Zurich)

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.

Suggested Citation

  • Simon D. Schwarz & Jianming Xu & Kapila Gunasekera & David Schürmann & Cathrine B. Vågbø & Elena Ferrari & Geir Slupphaug & Michael O. Hottiger & Primo Schär & Roland Steinacher, 2024. "Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44209-8
    DOI: 10.1038/s41467-023-44209-8
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    1. Luc Provencher & Wilson Nartey & Peter M. Brownlee & Austin W. Atkins & Jean-Philippe Gagné & Lou Baudrier & Nicholas S. Y. Ting & Cortt G. Piett & Shujuan Fang & Dustin D. Pearson & Shaun Moore & Pie, 2025. "CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair," Nature Communications, Nature, vol. 16(1), pages 1-24, December.

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