title: A new genotoxicity assay based on p53 target gene induction.
abstract: The p53 tumor suppressor protein has emerged as a universal sensor of genotoxic stress that regulates the transcription of numerous genes required for appropriate cellular response to DNA damage. Therefore, transcriptional induction of p53 target genes can be considered as a global and early indicator of genotoxic stress. By performing expression microarrays and RNA-Seq analysis on wild-type and mutant TP53 human lymphocytes respectively derived from controls and Li-Fraumeni patients and exposed to different classes of genotoxic agents, we first determined a common p53-dependent transcriptional signature of DNA damage. We then derived a simple and fast assay based on the exposure of wild-type TP53 lymphocytes to physical or chemical agents and on the quantitative measurement of selected p53 target gene transcriptional induction. The specificity of the p53 genotoxicity assay can easily be demonstrated by performing the same experiment in control lymphocytes with heterozygous TP53 mutations, which compromise responses to DNA damage. This assay allowed us to show that most of the drugs commonly used in cancer treatment, except the microtubule poisons, are highly genotoxic. The p53 genotoxicity assay should facilitate the measurement of the genotoxic effects of chemical and physical agents and the identification of drugs that are not genotoxic and do not expose patients to the risk of secondary malignancies, especially those with a constitutional defect in response to DNA damage, such as patients with Li-Fraumeni syndrome.
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen 76183, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Zerdoumi
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen 76183, France.
authors.forename: E
authors.initials: E
authors.lastname: Kasper
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen 76183, France.
authors.forename: F
authors.initials: F
authors.lastname: Soubigou
authors.affiliation: Inserm U905, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen 76183, France.
authors.forename: S
authors.initials: S
authors.lastname: Adriouch
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen 76183, France; Department of Genetics, Rouen University Hospital, Rouen 76183, France.
authors.forename: G
authors.initials: G
authors.lastname: Bougeard
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen 76183, France; Department of Genetics, Rouen University Hospital, Rouen 76183, France. Electronic address: frebourg@chu-rouen.fr.
authors.forename: T
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen 76183, France.
authors.forename: J-M
authors.initials: JM
authors.lastname: Flaman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000097:blood / Q000235:genetics; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D009152:Mutagenicity Tests / Q000379:methods*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D015533:Transcriptional Activation / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil
keywords: Cancer; Chemotherapy; DNA damage; Genotoxicity; Li-Fraumeni syndrome; TP53