Schwarz, Simon D; Xu, Jianming; Gunasekera, Kapila; Schürmann, David; Vågbø, Cathrine B; Ferrari, Elena; Slupphaug, Geir; Hottiger, Michael O; Schär, Primo; Steinacher, Roland (2024). Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation. Nature communications, 15(1), p. 184. Nature Publishing Group 10.1038/s41467-023-44209-8
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) |
UniBE Contributor: |
Gunasekera, Kapila |
Subjects: |
500 Science > 570 Life sciences; biology 500 Science > 540 Chemistry |
ISSN: |
2041-1723 |
Publisher: |
Nature Publishing Group |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
04 Jan 2024 11:59 |
Last Modified: |
14 Jan 2024 02:44 |
Publisher DOI: |
10.1038/s41467-023-44209-8 |
PubMed ID: |
38167803 |
BORIS DOI: |
10.48350/191168 |
URI: |
https://boris.unibe.ch/id/eprint/191168 |
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