Aflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation

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buir.contributor.authorGürsoy-Yüzügüllü, Özge
buir.contributor.authorYüzügüllü, Haluk
buir.contributor.authorYılmaz, Mustafa
buir.contributor.authorÖztürk, Mehmet
dc.citation.epage571en_US
dc.citation.issueNumber4en_US
dc.citation.spage561en_US
dc.citation.volumeNumber31en_US
dc.contributor.authorGürsoy-Yüzügüllü, Özgeen_US
dc.contributor.authorYüzügüllü, Haluken_US
dc.contributor.authorYılmaz, Mustafaen_US
dc.contributor.authorÖztürk, Mehmeten_US
dc.date.accessioned2016-02-08T09:53:50Z
dc.date.available2016-02-08T09:53:50Z
dc.date.issued2011en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.departmentGenetics and Biotechnology Research Center (BİLGEN)en_US
dc.description.abstractBackground: Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths. Aflatoxins, which may play a causative role in 5-28% of HCCs worldwide, are activated in liver cells and induce principally G→T mutations, including the TP53 codon 249(G→T) hotspot mutation. The DNA damage checkpoint response acts as an antitumour mechanism against genotoxic agents, but its role in aflatoxin-induced DNA damage is unknown. Aim: We studied the DNA damage checkpoint response of human cells to aflatoxin B1 (AFB1). Methods and results: The treatment of HepG2 hepatoma cells with mutation-inducing doses (3-5μmol/l) of AFB1 induced DNA adducts, 8-hydroxyguanine lesions and DNA strand breaks that lasted several days. Persistent phospho-H2AX and 53BP1 foci were also detected, but cell growth was not affected. AFB1-exposed HepG2 cells formed phospho-H2AX and 53BP1 foci, but failed to phosphorylate both Chk1 and Chk2. Huh7 hepatoma and HCT116 colorectal cancer cell lines also exhibited a similarly incomplete checkpoint response. p53 phosphorylation also failed, and AFB1-exposed cells did not show p53-dependent G1 arrest or a sustained G2/M arrest. These observations contrasted sharply with the fully functional DNA damage response of cells to Adriamycin. Cotreatment of cells with AFB1 did not inhibit p53 and p21Cip1 accumulation induced by Adriamycin. Thus, the deficient checkpoint response to AFB1 was not due to an inhibitory effect, but could be explained by an inefficient activation. Conclusion: Genotoxic doses of AFB1 induce an incomplete and inefficient checkpoint response in human cells. This defective response may contribute to the mutagenic and carcinogenic potencies of aflatoxins.en_US
dc.identifier.doi10.1111/j.1478-3231.2011.02474.xen_US
dc.identifier.issn1478-3223
dc.identifier.urihttp://hdl.handle.net/11693/21978
dc.language.isoEnglishen_US
dc.publisherJohn Wiley & Sonsen_US
dc.relation.isversionofhttp://dx.doi.org/10.1111/j.1478-3231.2011.02474.xen_US
dc.source.titleLiver Internationalen_US
dc.subjectAflatoxinen_US
dc.subjectCheckpointen_US
dc.subjectDNA damage responseen_US
dc.subjectLiver canceren_US
dc.subjectp53en_US
dc.titleAflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activationen_US
dc.typeArticleen_US
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