2. Academic Validation
  3. Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation

Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation

  • Nat Commun. 2024 Jan 2;15(1):184. doi: 10.1038/s41467-023-44209-8.
Simon D Schwarz # 1,  Jianming Xu # 1 2,  Kapila Gunasekera 2 3,  David Schürmann 1,  Cathrine B Vågbø 4,  Elena Ferrari 2,  Geir Slupphaug 4,  Michael O Hottiger 2,  Primo Schär 5,  Roland Steinacher 6 7
Affiliations

Affiliations

  • 1 Department of Biomedicine, University of Basel, Basel, Switzerland.
  • 2 Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
  • 3 Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland.
  • 4 Proteomics and Modomics Experimental Core Facility (PROMEC), Norwegian University of Science and Technology and St. Olavs Hospital, Trondheim, Norway.
  • 5 Department of Biomedicine, University of Basel, Basel, Switzerland. [email protected].
  • 6 Department of Biomedicine, University of Basel, Basel, Switzerland. [email protected].
  • 7 Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. [email protected].
  • # Contributed equally.
PMID: 38167803 DOI: 10.1038/s41467-023-44209-8
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.

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