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Mammalian N1-adenosine PARylation is a reversible DNA modification

Author

Listed:
  • Michael U. Musheev

    (Institute of Molecular Biology (IMB))

  • Lars Schomacher

    (Institute of Molecular Biology (IMB))

  • Amitava Basu

    (Institute of Molecular Biology (IMB))

  • Dandan Han

    (Institute of Molecular Biology (IMB)
    STEMCELL Technologies Germany GmbH)

  • Laura Krebs

    (Institute of Molecular Biology (IMB))

  • Carola Scholz

    (Institute of Molecular Biology (IMB))

  • Christof Niehrs

    (Institute of Molecular Biology (IMB)
    DKFZ-ZMBH Alliance)

Abstract

Poly-ADP-ribosylation (PARylation) is regarded as a protein-specific modification. However, some PARPs were recently shown to modify DNA termini in vitro. Here, we use ultrasensitive mass spectrometry (LC-MS/MS), anti-PAR antibodies, and anti-PAR reagents to show that mammalian DNA is physiologically PARylated and to different levels in primary tissues. Inhibition of PAR glycohydrolase (PARG) increases DNA PARylation, supporting that the modification is reversible. DNA PARylation requires PARP1 and in vitro PARP1 PARylates single-stranded DNA, while PARG reverts the modification. DNA PARylation occurs at the N1-position of adenosine residues to form N1-Poly(ADP-ribosyl)-deoxyadenosine. Through partial hydrolysis of mammalian gDNA we identify PAR-DNA via the diagnostic deamination product N1-ribosyl-deoxyinosine to occur in vivo. The discovery of N1-adenosine PARylation as a DNA modification establishes the conceptual and methodological framework to elucidate its biological relevance and extends the role of PARP enzymes.

Suggested Citation

  • Michael U. Musheev & Lars Schomacher & Amitava Basu & Dandan Han & Laura Krebs & Carola Scholz & Christof Niehrs, 2022. "Mammalian N1-adenosine PARylation is a reversible DNA modification," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33731-w
    DOI: 10.1038/s41467-022-33731-w
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    1. Marion Schuller & Rachel E. Butler & Antonio Ariza & Callum Tromans-Coia & Gytis Jankevicius & Tim D. W. Claridge & Sharon L. Kendall & Shan Goh & Graham R. Stewart & Ivan Ahel, 2021. "Molecular basis for DarT ADP-ribosylation of a DNA base," Nature, Nature, vol. 596(7873), pages 597-602, August.
    2. Jerry H. Houl & Zu Ye & Chris A. Brosey & Lakshitha P. F. Balapiti-Modarage & Sarita Namjoshi & Albino Bacolla & Daniel Laverty & Brian L. Walker & Yasin Pourfarjam & Leslie S. Warden & Naga Babu Chin, 2019. "Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
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