title: 6-Thioguanine damages mitochondrial DNA and causes mitochondrial dysfunction in human cells.
abstract: The anticancer and immunosuppressant thiopurines cause 6-thioguanine (6-TG) to accumulate in nuclear DNA. We report that 6-TG is also readily incorporated into mitochondrial DNA (mtDNA) where it is rapidly oxidized. The oxidized forms of mtDNA 6-TG inhibit replication by DNA Pol-γ. Accumulation of oxidized 6-TG is associated with reduced mtDNA transcription, a decline in mitochondrial protein levels, and loss of mitochondrial function. Ultraviolet A radiation (UVA) also oxidizes mtDNA 6-TG. Cells without mtDNA are less sensitive to killing by a combination of 6-TG and UVA than their mtDNA-containing counterparts, indicating that photochemical mtDNA 6-TG oxidation contributes to 6-TG-mediated UVA photosensitization.
authors: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts, UK. ilse.daehn@mssm.edu
authors: Ilse
authors: I
authors: Daehn
authors: Reto
authors: R
authors: Brem
authors: Eva
authors: E
authors: Barkauskaite
authors: Peter
authors: P
authors: Karran
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D045325:HCT116 Cells; D006801:Humans; D007700:Kinetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D010084:Oxidation-Reduction; D013866:Thioguanine / Q000009:adverse effects* / Q000378:metabolism; D013997:Time Factors; D014466:Ultraviolet Rays
chemical_list: D004272:DNA, Mitochondrial; D000255:Adenosine Triphosphate; D013866:Thioguanine