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Impact of the Cellular Zinc Status on PARP-1 Activity and Genomic Stability in HeLa S3 Cells

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Impact of the Cellular Zinc Status on PARP-1 Activity and Genomic Stability in HeLa S3 Cells

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WEDLER, Nadin, Tizia MATTHÄUS, Bettina STRAUCH, Elena DILGER, Martin WATERSTRAAT, Aswin MANGERICH, Andrea HARTWIG, 2021. Impact of the Cellular Zinc Status on PARP-1 Activity and Genomic Stability in HeLa S3 Cells. In: Chemical Research in Toxicology. American Chemical Society (ACS). 34(3), pp. 839-848. ISSN 0893-228X. eISSN 1520-5010. Available under: doi: 10.1021/acs.chemrestox.0c00452

@article{Wedler2021-03-15Impac-53071, title={Impact of the Cellular Zinc Status on PARP-1 Activity and Genomic Stability in HeLa S3 Cells}, year={2021}, doi={10.1021/acs.chemrestox.0c00452}, number={3}, volume={34}, issn={0893-228X}, journal={Chemical Research in Toxicology}, pages={839--848}, author={Wedler, Nadin and Matthäus, Tizia and Strauch, Bettina and Dilger, Elena and Waterstraat, Martin and Mangerich, Aswin and Hartwig, Andrea} }

Hartwig, Andrea Wedler, Nadin Matthäus, Tizia Poly(ADP-ribose) polymerase 1 (PARP-1) is actively involved in several DNA repair pathways, especially in the detection of DNA lesions and DNA damage signaling. However, the mechanisms of PARP-1 activation are not fully understood. PARP-1 contains three zinc finger structures, among which the first zinc finger has a remarkably low affinity toward zinc ions. Within the present study, we investigated the impact of the cellular zinc status on PARP-1 activity and on genomic stability in HeLa S3 cells. Significant impairment of H<sub>2</sub>O<sub>2</sub>-induced poly(ADP-ribosyl)ation and an increase in DNA strand breaks were detected in the case of zinc depletion by the zinc chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) which reduced the total and labile zinc concentrations. On the contrary, preincubation of cells with ZnCl2 led to an overload of total as well as labile zinc and resulted in an increased poly(ADP-ribosyl)ation response upon H2O2 treatment. Furthermore, the impact of the cellular zinc status on gene expression profiles was investigated via high-throughput RT-qPCR, analyzing 95 genes related to metal homeostasis, DNA damage and oxidative stress response, cell cycle regulation and proliferation. Genes encoding metallothioneins responded most sensitively on conditions of mild zinc depletion or moderate zinc overload. Zinc depletion induced by higher concentrations of TPEN led to a significant induction of genes encoding DNA repair factors and cell cycle arrest, indicating the induction of DNA damage and genomic instability. Zinc overload provoked an up-regulation of the oxidative stress response. Altogether, the results highlight the potential role of zinc signaling for PARP-1 activation and the maintenance of genomic stability. Mangerich, Aswin Hartwig, Andrea Strauch, Bettina Matthäus, Tizia Dilger, Elena Strauch, Bettina 2021-03-03T16:23:08Z Mangerich, Aswin Waterstraat, Martin Impact of the Cellular Zinc Status on PARP-1 Activity and Genomic Stability in HeLa S3 Cells Waterstraat, Martin 2021-03-03T16:23:08Z 2021-03-15 Wedler, Nadin terms-of-use eng Dilger, Elena

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