ArticleNucleic acids research2022
PARP inhibitors trap PARP2 and alter the mode of recruitment of PARP2 at DNA damage sites.
Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 51 citations in OpenAlex.
- Structural basis of PARP2 recognition of nucleosomal DNA breaks and inhibitor trapping.Nucleic acids research · 2026Article
- Effects of a cancer-associated mutation and multiple serine phosphorylation on poly(ADP-ribose) polymerase 2.Biophysical journal · 2026Article
- Linkerability of Protein Ligands: Insights From Cocrystal Structures and Implications for DNA-Encoded Libraries.Molecular informatics · 2026Article
- Ku70-SAP domain has an overlapping function with DNA-PKcs in limiting the lateral movement of the Ku ring along DNA.Nucleic acids research · 2026Article
- Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies.Molecules (Basel, Switzerland) · 2026Review
- Deciphering the dark side of histone ADP-ribosylation: what structural features of damaged nucleosome regulate the activities of PARP1 and PARP2.Nucleic acids research · 2025Article
- A PARP2 active site helix melts to permit DNA damage-induced enzymatic activation.Molecular cell · 2025Article
- XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to DNA damage sites.Nucleic acids research · 2025Article
- Article
- Inactive Parp2 causes Tp53-dependent lethal anemia by blocking replication-associated nick ligation in erythroblasts.Molecular cell · 2024Article
- Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions.Biomolecules · 2024Review
- Redundant but essential functions of PARP1 and PARP2 in DNA ligase I-independent DNA replication.Nucleic acids research · 2024Article
- The dynamics and regulation of PARP1 and PARP2 in response to DNA damage and during replication.DNA repair · 2024Review
- The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity.Nucleic acids research · 2024Article
- A PARP2-specific active site α-helix melts to permit DNA damage-induced enzymatic activation.bioRxiv : the preprint server for biology · 2024Article
- Specific and shared biological functions of PARP2 - is PARP2 really a lil' brother of PARP1?Expert reviews in molecular medicine · 2024Review
- Immunomodulatory roles of PARPs: Shaping the tumor microenvironment, one ADP-ribose at a time.Current opinion in chemical biology · 2023Review
- Review
- Review
- Poly(ADP-Ribose) Polymerase-1 Lacking Enzymatic Activity Is Not Compatible with Mouse Development.Cells · 2023Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Dual-inhibitors of PARP1 and PARP2 are promising anti-cancer drugs. In addition to blocking PARP1&2 enzymatic activity, PARP inhibitors also extend the lifetime of DNA damage-induced PARP1&2 foci, termed trapping. Trapping is important for the therapeutic effects of PARP inhibitors. Using live-cell imaging, we found that PARP inhibitors cause persistent PARP2 foci by switching the mode of PARP2 recruitment from a predominantly PARP1- and PAR-dependent rapid exchange to a WGR domain-mediated stalling of PARP2 on DNA. Specifically, PARP1-deletion markedly reduces but does not abolish PARP2 foci. The residual PARP2 foci in PARP1-deficient cells are DNA-dependent and abrogated by the R140A mutation in the WGR domain. Yet, PARP2-R140A forms normal foci in PARP1-proficient cells. In PARP1-deficient cells, PARP inhibitors - niraparib, talazoparib, and, to a lesser extent, olaparib - enhance PARP2 foci by preventing PARP2 exchange. This trapping of PARP2 is independent of auto-PARylation and is abolished by the R140A mutation in the WGR domain and the H415A mutation in the catalytic domain. Taken together, we found that PARP inhibitors trap PARP2 by physically stalling PARP2 on DNA via the WGR-DNA interaction while suppressing the PARP1- and PAR-dependent rapid exchange of PARP2.
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