PARP1-dependent DNA-protein crosslink repair

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, Michael L. Nielsen, Keith Caldecott and Julien P. Duxin ()
Additional contact information
Zita Fábián: University of Copenhagen
Ellen S. Kakulidis: 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
Junhui Wang: Falmer
Xueyuan Leng: 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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-50912-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50912-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-50912-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().