title: A mechanism for 1,4-Benzoquinone-induced genotoxicity.
abstract: Benzene is a common environmental toxin and its metabolite, 1-4-Benzoquinone (BQ) causes hematopoietic cancers like myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). BQ has not been comprehensively assessed for its impact on genome maintenance, limiting our understanding of the true health risks associated with benzene exposure and our ability to identify people with increased sensitivity to this genotoxin. Here we analyze the impact BQ exposure has on wild type and DNA repair-defective mouse embryonic stem (ES) cells and wild type human cells. We find that double strand break (DSB) repair and replication fork maintenance pathways including homologous recombination (HR) and Fanconi anemia (FA) suppress BQ toxicity. BQ-induced damage efficiently stalls replication forks, yet poorly induces ATR/DNA-PKCS responses. Furthermore, the pattern of BQ-induced γH2AX and 53BP1foci is consistent with the formation of poly(ADP-ribose) polymerase 1 (PARP1)-stabilized regressed replication forks. At a biochemical level, BQ inhibited topoisomerase 1 (topo1)-mediated DNA ligation and nicking in vitro; thus providing mechanism for the cellular phenotype. These data are consistent with a model that proposes BQ interferes with type I topoisomerase's ability to maintain replication fork restart and progression leading to chromosomal instability that has the potential to cause hematopoietic cancers like MDS and AML.
authors.affiliation: Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Son
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau SAR, China.
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.affiliation: Department of Genetics, Cancer Genomics Netherlands, Erasmus MC, The Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Hoeijmarkers
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|The Cancer Therapy Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|The Barshop Center of Aging, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|Greehey Children's Cancer Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|Current address: BioAffinity, San Antonio, Texas, USA.
authors.forename: Vivienne I
authors.initials: VI
authors.lastname: Rebel
authors.affiliation: Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|The Cancer Therapy Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|The Barshop Center of Aging, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hasty
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009153:Mutagens / Q000633:toxicity*
chemical_list: D016227:Benzoquinones; D009153:Mutagens; C004532:quinone
keywords: Fanconi anemia; double strand break repair; replication fork maintenance; type 1 topoisomerase