title: Low doses of ultraviolet radiation and oxidative damage induce dramatic accumulation of mitochondrial DNA replication intermediates, fork regression, and replication initiation shift.
abstract: Mitochondrial DNA is prone to damage by various intrinsic as well as environmental stressors. DNA damage can in turn cause problems for replication, resulting in replication stalling and double-strand breaks, which are suspected to be the leading cause of pathological mtDNA rearrangements. In this study, we exposed cells to subtle levels of oxidative stress or UV radiation and followed their effects on mtDNA maintenance. Although the damage did not influence mtDNA copy number, we detected a massive accumulation of RNA:DNA hybrid-containing replication intermediates, followed by an increase in cruciform DNA molecules, as well as in bidirectional replication initiation outside of the main replication origin, OH. Our results suggest that mitochondria maintain two different types of replication as an adaptation to different cellular environments; the RNA:DNA hybrid-involving replication mode maintains mtDNA integrity in tissues with low oxidative stress, and the potentially more error tolerant conventional strand-coupled replication operates when stress is high.
authors.affiliation: Department of Biology, University of Eastern Finland, 80101 Joensuu, Finland.
authors.forename: Rubén
authors.initials: R
authors.lastname: Torregrosa-Muñumer
authors.affiliation: Department of Biology, University of Eastern Finland, 80101 Joensuu, Finland.
authors.forename: Steffi
authors.initials: S
authors.lastname: Goffart
authors.affiliation: Department of Biology, University of Eastern Finland, 80101 Joensuu, Finland.
authors.forename: Juha A
authors.initials: JA
authors.lastname: Haikonen
authors.affiliation: Department of Biology, University of Eastern Finland, 80101 Joensuu, Finland Jaakko.Pohjoismaki@uef.fi.
authors.forename: Jaakko L O
authors.initials: JL
authors.lastname: Pohjoismäki
mesh_terms: D002478:Cells, Cultured; D056915:DNA Copy Number Variations; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000502:physiology / Q000528:radiation effects*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D057809:HEK293 Cells; D006801:Humans; D009693:Nucleic Acid Hybridization; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D018741:Replication Origin / Q000502:physiology / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D004272:DNA, Mitochondrial; D012313:RNA