title: Genotoxicity of alcohol is linked to DNA replication-associated damage and homologous recombination repair.
abstract: Although alcohol consumption is related to increased cancer risk, its molecular mechanism remains unclear. Here, we demonstrate that an intake of 10% alcohol for 4 weeks in rats is genotoxic due to induction of micronuclei. Acetaldehyde (AA), the first product of ethanol metabolism, is believed to be responsible for DNA damage induced by alcohol. Here, we observe that AA effectively blocks DNA replication elongation in mammalian cells, resulting in DNA double-strand breaks associated with replication. AA-induced DNA damage sites colocalize with the homologous recombination (HR) repair protein RAD51. HR measured in the hypoxhantineguaninefosforibosyltransferase (HPRT) gene is effectively induced by AA and recombination defective mammalian cells are hypersensitive to AA, clearly demonstrating that HR is essential in the repair of AA-induced DNA damage. Altogether, our data indicate that alcohol genotoxicity related to AA produces replication lesions on DNA triggering HR repair.
authors.affiliation: Department of Genetics, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kotova
authors.forename: Daniel
authors.initials: D
authors.lastname: Vare
authors.forename: Niklas
authors.initials: N
authors.lastname: Schultz
authors.forename: Dobroslawa
authors.initials: D
authors.lastname: Gradecka Meesters
authors.forename: Maciej
authors.initials: M
authors.lastname: Stepnik
authors.forename: Jan
authors.initials: J
authors.lastname: Grawé
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: Dag
authors.initials: D
authors.lastname: Jenssen
mesh_terms: D000079:Acetaldehyde / Q000633:toxicity*; D000438:Alcohols / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042822:Genomic Instability / Q000187:drug effects; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D015162:Micronucleus Tests; D051135:Rad51 Recombinase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011995:Recombination, Genetic / Q000187:drug effects*; D059767:Recombinational DNA Repair / Q000187:drug effects*
chemical_list: D000438:Alcohols; D051135:Rad51 Recombinase; D000079:Acetaldehyde