Gutenberg Open Science: DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-7401

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DC Field	Value	Language
dc.contributor.author	Mimmler, Maximilian	-
dc.contributor.author	Peter, Simon	-
dc.contributor.author	Kraus, Alexander	-
dc.contributor.author	Stroh, Svenja	-
dc.contributor.author	Nikolova, Teodora	-
dc.contributor.author	Seiwert, Nina	-
dc.contributor.author	Hasselwander, Solveig	-
dc.contributor.author	Neitzel, Carina	-
dc.contributor.author	Haub, Jessica	-
dc.contributor.author	Monien, Bernhard H.	-
dc.contributor.author	Nicken, Petra	-
dc.contributor.author	Steinberg, Pablo	-
dc.contributor.author	Shay, Jerry W.	-
dc.contributor.author	Kaina, Bernd	-
dc.contributor.author	Fahrer, Jörg	-
dc.date.accessioned	2022-07-13T10:13:01Z	-
dc.date.available	2022-07-13T10:13:01Z	-
dc.date.issued	2016
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/7415	-
dc.description.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.	en_GB
dc.description.sponsorship	DFG, Open Access-Publizieren Universität Mainz / Universitätsmedizin	de
dc.language.iso	eng	de
dc.rights	CC BY-NC	*
dc.rights.uri	https://creativecommons.org/licenses/by-nc/4.0/	*
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-7401	-
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.number	2700	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Nucleic acids research	de
jgu.journal.volume	44	de
jgu.journal.issue	21	de
jgu.pages.start	10259	de
jgu.pages.end	10276	de
jgu.publisher.year	2016	-
jgu.publisher.name	Oxford Univ. Press	de
jgu.publisher.place	Oxford	de
jgu.publisher.uri	http://dx.doi.org/10.1093/nar/gkw791	de
jgu.publisher.issn	1362-4962	de
jgu.publisher.issn	0305-1048	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	610	de
opus.date.modified	2018-08-23T08:52:20Z
opus.subject.dfgcode	00-000
opus.organisation.string	FB 04: Medizin: Institut für Toxikologie	de_DE
opus.identifier.opusid	56409
opus.institute.number	0414
opus.metadataonly	false
opus.type.contenttype	Keine	de_DE
opus.type.contenttype	None	en_EN
opus.affiliated	Nikolova, Teodora
opus.affiliated	Kaina, Bernd
opus.affiliated	Fahrer, Jörg
jgu.publisher.doi	10.1093/nar/gkw791	de
jgu.organisation.ror	https://ror.org/023b0x485	-
Appears in collections:	DFG-OA-Publizieren (2012 - 2017)

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