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PARP1-dependent DNA-protein crosslink repair.
- Source :
-
Nature communications [Nat Commun] 2024 Aug 05; Vol. 15 (1), pp. 6641. Date of Electronic Publication: 2024 Aug 05. - Publication Year :
- 2024
-
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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Xenopus laevis
Ubiquitination
Humans
DNA metabolism
DNA Damage
Camptothecin pharmacology
Protein Processing, Post-Translational
DNA, Single-Stranded metabolism
Xenopus Proteins metabolism
DNA Repair
Poly (ADP-Ribose) Polymerase-1 metabolism
Poly (ADP-Ribose) Polymerase-1 genetics
DNA Topoisomerases, Type I metabolism
Poly ADP Ribosylation
DNA Replication
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39103378
- Full Text :
- https://doi.org/10.1038/s41467-024-50912-x