title: Apoptosis induced by persistent single-strand breaks in mitochondrial genome: critical role of EXOG (5'-EXO/endonuclease) in their repair.
abstract: Reactive oxygen species (ROS), continuously generated as by-products of respiration, inflict more damage on the mitochondrial (mt) than on the nuclear genome because of the nonchromatinized nature and proximity to the ROS source of the mitochondrial genome. Such damage, particularly single-strand breaks (SSBs) with 5'-blocking deoxyribose products generated directly or as repair intermediates for oxidized bases, is repaired via the base excision/SSB repair pathway in both nuclear and mt genomes. Here, we show that EXOG, a 5'-exo/endonuclease and unique to the mitochondria unlike FEN1 or DNA2, which, like EXOG, has been implicated in the removal of the 5'-blocking residue, is required for repairing endogenous SSBs in the mt genome. EXOG depletion induces persistent SSBs in the mtDNA, enhances ROS levels, and causes apoptosis in normal cells but not in mt genome-deficient rho0 cells. Thus, these data show for the first time that persistent SSBs in the mt genome alone could provide the initial trigger for apoptotic signaling in mammalian cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555-1079, USA.
authors.forename: Anne W
authors.initials: AW
authors.lastname: Tann
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
authors.forename: Gregor
authors.initials: G
authors.lastname: Meiss
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.forename: Sankar
authors.initials: S
authors.lastname: Mitra
authors.forename: Bartosz
authors.initials: B
authors.lastname: Szczesny
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism*; D054629:Genome, Mitochondrial / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D005092:Exonucleases