title: Susceptibility to bystander DNA damage is influenced by replication and transcriptional activity.
abstract: Direct cellular DNA damage may lead to genome destabilization in unexposed, bystander, cells sharing the same milieu with directly damaged cells by means of the bystander effect. One proposed mechanism involves double strand break (DSB) formation in S phase cells at sites of single strand lesions in the DNA of replication complexes, which has a more open structure compared with neighboring DNA. The DNA in transcription complexes also has a more open structure, and hence may be susceptible to bystander DSB formation from single strand lesions. To examine whether transcription predisposes non-replicating cells to bystander effect-induced DNA DSBs, we examined two types of primary cells that exhibit high levels of transcription in the absence of replication, rat neurons and human lymphocytes. We found that non-replicating bystander cells with high transcription rates exhibited substantial levels of DNA DSBs, as monitored by γ-H2AX foci formation. Additionally, as reported in proliferating cells, TGF-β and NO were found to mimic bystander effects in cell populations lacking DNA synthesis. These results indicate that cell vulnerability to bystander DSB damage may result from transcription as well as replication. The findings offer insights into which tissues may be vulnerable to bystander genomic destabilization in vivo.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20952, USA. Jennifer.Dickey@fda.hhs.gov
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Dickey
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Baird
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Redon
authors.forename: Valeriya
authors.initials: V
authors.lastname: Avdoshina
authors.forename: Guillermo
authors.initials: G
authors.lastname: Palchik
authors.forename: Junfang
authors.initials: J
authors.lastname: Wu
authors.forename: Alexei
authors.initials: A
authors.lastname: Kondratyev
authors.forename: William M
authors.initials: WM
authors.lastname: Bonner
authors.forename: Olga A
authors.initials: OA
authors.lastname: Martin
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D024201:Bystander Effect; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide