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PARP1-dependent DNA-protein crosslink repair

Author

Listed:
  • Zita Fábián

    (University of Copenhagen)

  • Ellen S. Kakulidis

    (University of Copenhagen
    University of Copenhagen)

  • Ivo A. Hendriks

    (University of Copenhagen)

  • Ulrike Kühbacher

    (University of Copenhagen)

  • Nicolai B. Larsen

    (University of Copenhagen)

  • Marta Oliva-Santiago

    (University of Copenhagen
    University of Copenhagen)

  • Junhui Wang

    (Falmer)

  • Xueyuan Leng

    (University of Copenhagen
    University of Copenhagen)

  • A. Barbara Dirac-Svejstrup

    (University of Copenhagen)

  • Jesper Q. Svejstrup

    (University of Copenhagen)

  • Michael L. Nielsen

    (University of Copenhagen)

  • Keith Caldecott

    (Falmer)

  • Julien P. Duxin

    (University of Copenhagen
    University of Copenhagen)

Abstract

DNA-protein crosslinks (DPCs) are toxic lesions that inhibit DNA related processes. Post-translational modifications (PTMs), including SUMOylation and ubiquitylation, play a central role in DPC resolution, but whether other PTMs are also involved remains elusive. Here, we identify a DPC repair pathway orchestrated by poly-ADP-ribosylation (PARylation). Using Xenopus egg extracts, we show that DPCs on single-stranded DNA gaps can be targeted for degradation via a replication-independent mechanism. During this process, DPCs are initially PARylated by PARP1 and subsequently ubiquitylated and degraded by the proteasome. Notably, PARP1-mediated DPC resolution is required for resolving topoisomerase 1-DNA cleavage complexes (TOP1ccs) induced by camptothecin. Using the Flp-nick system, we further reveal that in the absence of PARP1 activity, the TOP1cc-like lesion persists and induces replisome disassembly when encountered by a DNA replication fork. In summary, our work uncovers a PARP1-mediated DPC repair pathway that may underlie the synergistic toxicity between TOP1 poisons and PARP inhibitors.

Suggested Citation

  • Zita Fábián & Ellen S. Kakulidis & Ivo A. Hendriks & Ulrike Kühbacher & Nicolai B. Larsen & Marta Oliva-Santiago & Junhui Wang & Xueyuan Leng & A. Barbara Dirac-Svejstrup & Jesper Q. Svejstrup & Micha, 2024. "PARP1-dependent DNA-protein crosslink repair," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50912-x
    DOI: 10.1038/s41467-024-50912-x
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    References listed on IDEAS

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