Autoren:	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
Titel:	DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP
Online-Publikationsdatum:	13-Jul-2022
Erscheinungsdatum:	2016
Sprache des Dokuments:	Englisch
Zusammenfassung/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-Sachgruppe:	610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-7401
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY-NC
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by-nc/4.0/
Zeitschrift:	Nucleic acids research 44 21
Seitenzahl oder Artikelnummer:	10259 10276
Verlag:	Oxford Univ. Press
Verlagsort:	Oxford
Erscheinungsdatum:	2016
ISSN:	1362-4962 0305-1048
URL der Originalveröffentlichung:	http://dx.doi.org/10.1093/nar/gkw791
DOI der Originalveröffentlichung:	10.1093/nar/gkw791
Enthalten in den Sammlungen:	DFG-OA-Publizieren (2012 - 2017)