PARP1 and XRCC1 exhibit a reciprocal relationship in genotoxic stress response

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2023
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Cell Biology and Toxicology. Springer. 2023, 39, pp. 345-364. ISSN 0742-2091. eISSN 1573-6822. Available under: doi: 10.1007/s10565-022-09739-9
Zusammenfassung

PARP1 (aka ARTD1) acts as a prime sensor of cellular genotoxic stress response. PARP1 detects DNA strand breaks and subsequently catalyzes the formation of poly(ADP-ribose) (PAR), which leads to the recruitment of the scaffold protein XRCC1 during base excision and single strand break repair and the assembly of multi-protein complexes to promote DNA repair. Here, we reveal that the recruitment of either protein to sites of DNA damage is impeded in the absence of the other, indicating a strong reciprocal relationship between the two DNA repair factors during genotoxic stress response. We further analyzed several cellular and molecular endpoints in HeLa PARP1 KO, XRCC1 KO, and PARP1/XRCC1 double KO (DKO) cells after genotoxic treatments, i.e., PARylation response, NAD+ levels, clonogenic survival, cell cycle progression, cell death, and DNA repair. The analysis of NAD+ levels and cytotoxicity after treatment with the topoisomerase I inhibitor camptothecin revealed a hypersensitivity phenotype of XRCC1 KO cells compared to PARP1 KO cells-an effect that could be rescued by the additional genetic deletion of PARP1 as well as by pharmacological PARP inhibition. Moreover, impaired repair of hydrogen peroxide and CPT-induced DNA damage in XRCC1 KO cells could be partially rescued by additional deletion of PARP1. Our results therefore highlight important reciprocal regulatory functions of XRCC1 and PARP1 during genotoxic stress response.

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570 Biowissenschaften, Biologie
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PARP1, ARTD, Poly(ADP-ribosyl)ation, XRCC1, Camptothecin
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ISO 690REBER, Julia M., Jovana BOŽIĆ-PETKOVIĆ, Michelle LIPPMANN, Marvin MAZZARDO, Asisa DILGER, Rebecca WARMERS, Alexander BÜRKLE, Aswin MANGERICH, 2023. PARP1 and XRCC1 exhibit a reciprocal relationship in genotoxic stress response. In: Cell Biology and Toxicology. Springer. 2023, 39, pp. 345-364. ISSN 0742-2091. eISSN 1573-6822. Available under: doi: 10.1007/s10565-022-09739-9
BibTex
@article{Reber2023PARP1-57933,
  year={2023},
  doi={10.1007/s10565-022-09739-9},
  title={PARP1 and XRCC1 exhibit a reciprocal relationship in genotoxic stress response},
  volume={39},
  issn={0742-2091},
  journal={Cell Biology and Toxicology},
  pages={345--364},
  author={Reber, Julia M. and Božić-Petković, Jovana and Lippmann, Michelle and Mazzardo, Marvin and Dilger, Asisa and Warmers, Rebecca and Bürkle, Alexander and Mangerich, Aswin},
  note={German Research Foundation (DFG, grant number MA-4905/4–1)}
}
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    <dcterms:abstract xml:lang="eng">PARP1 (aka ARTD1) acts as a prime sensor of cellular genotoxic stress response. PARP1 detects DNA strand breaks and subsequently catalyzes the formation of poly(ADP-ribose) (PAR), which leads to the recruitment of the scaffold protein XRCC1 during base excision and single strand break repair and the assembly of multi-protein complexes to promote DNA repair. Here, we reveal that the recruitment of either protein to sites of DNA damage is impeded in the absence of the other, indicating a strong reciprocal relationship between the two DNA repair factors during genotoxic stress response. We further analyzed several cellular and molecular endpoints in HeLa PARP1 KO, XRCC1 KO, and PARP1/XRCC1 double KO (DKO) cells after genotoxic treatments, i.e., PARylation response, NAD&lt;sup&gt;+&lt;/sup&gt; levels, clonogenic survival, cell cycle progression, cell death, and DNA repair. The analysis of NAD&lt;sup&gt;+&lt;/sup&gt; levels and cytotoxicity after treatment with the topoisomerase I inhibitor camptothecin revealed a hypersensitivity phenotype of XRCC1 KO cells compared to PARP1 KO cells-an effect that could be rescued by the additional genetic deletion of PARP1 as well as by pharmacological PARP inhibition. Moreover, impaired repair of hydrogen peroxide and CPT-induced DNA damage in XRCC1 KO cells could be partially rescued by additional deletion of PARP1. Our results therefore highlight important reciprocal regulatory functions of XRCC1 and PARP1 during genotoxic stress response.</dcterms:abstract>
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