Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-7401
Authors: | Mimmler, Maximilian Peter, Simon Kraus, Alexander Stroh, Svenja Nikolova, Teodora Seiwert, Nina Hasselwander, Solveig Neitzel, Carina Haub, Jessica Monien, Bernhard H. Nicken, Petra Steinberg, Pablo Shay, Jerry W. Kaina, Bernd Fahrer, Jörg |
Title: | DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP |
Online publication date: | 13-Jul-2022 |
Year of first publication: | 2016 |
Language: | english |
Abstract: | PhIP is an abundant heterocyclic aromatic amine (HCA) and important dietary carcinogen. Following metabolic activation, PhIP causes bulky DNA lesions at the C8-position of guanine. Although C8-PhIP-dG adducts are mutagenic, their interference with the DNA replication machinery and the elicited DNA damage response (DDR) have not yet been studied. Here, we analyzed PhIP-triggered replicative stress and elucidated the role of the apical DDR kinases ATR, ATM and DNA-PKcs in the cellular defense response. First, we demonstrate that PhIP induced C8-PhIP-dG adducts and DNA strand breaks. This stimulated ATR-CHK1 signaling, phosphorylation of histone 2AX and the formation of RPA foci. In proliferating cells, PhIP treatment increased the frequency of stalled replication forks and reduced fork speed. Inhibition of ATR in the presence of PhIP-induced DNA damage strongly promoted the formation of DNA double-strand breaks, activation of the ATM-CHK2 pathway and hyperphosphorylation of RPA. The abrogation of ATR signaling potentiated the cell death response and enhanced chromosomal aberrations after PhIP treatment, while ATM and DNA-PK inhibition had only marginal effects. These results strongly support the notion that ATR plays a key role in the defense against cancer formation induced by PhIP and related HCAs. |
DDC: | 610 Medizin 610 Medical sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 04 Medizin |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-7401 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY-NC |
Information on rights of use: | https://creativecommons.org/licenses/by-nc/4.0/ |
Journal: | Nucleic acids research 44 21 |
Pages or article number: | 10259 10276 |
Publisher: | Oxford Univ. Press |
Publisher place: | Oxford |
Issue date: | 2016 |
ISSN: | 1362-4962 0305-1048 |
Publisher URL: | http://dx.doi.org/10.1093/nar/gkw791 |
Publisher DOI: | 10.1093/nar/gkw791 |
Appears in collections: | DFG-OA-Publizieren (2012 - 2017) |
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![]() | dna_damage_response_curtails_-20220712205313823.pdf | 5.92 MB | Adobe PDF | View/Open |