title: The contribution of mitochondrial thymidylate synthesis in preventing the nuclear genome stress.
abstract: In quiescent fibroblasts, the expression levels of cytosolic enzymes for thymidine triphosphate (dTTP) synthesis are down-regulated, causing a marked reduction in the dTTP pool. In this study, we provide evidence that mitochondrial thymidylate synthesis via thymidine kinase 2 (TK2) is a limiting factor for the repair of ultraviolet (UV) damage in the nuclear compartment in quiescent fibroblasts. We found that TK2 deficiency causes secondary DNA double-strand breaks formation in the nuclear genome of quiescent cells at the late stage of recovery from UV damage. Despite slower repair of quiescent fibroblast deficient in TK2, DNA damage signals eventually disappeared, and these cells were capable of re-entering the S phase after serum stimulation. However, these cells displayed severe genome stress as revealed by the dramatic increase in 53BP1 nuclear body in the G1 phase of the successive cell cycle. Here, we conclude that mitochondrial thymidylate synthesis via TK2 plays a role in facilitating the quality repair of UV damage for the maintenance of genome integrity in the cells that are temporarily arrested in the quiescent state.
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan (R.O.C.), Department of Anatomy, Physiology and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, S-751 23 Uppsala, Sweden and Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan (R.O.C.).
authors.forename: Ming-Hsiang
authors.initials: MH
authors.lastname: Lee
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.forename: Zee-Fen
authors.initials: ZF
authors.lastname: Chang
mesh_terms: D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D003854:Deoxyribonucleotides / Q000378:metabolism; D016678:Genome; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D008928:Mitochondria / Q000201:enzymology*; D013312:Stress, Physiological / Q000235:genetics*; D013937:Thymidine Kinase / Q000378:metabolism / Q000502:physiology*; D013942:Thymine Nucleotides / Q000096:biosynthesis*; D000071857:Tumor Suppressor p53-Binding Protein 1; D014466:Ultraviolet Rays
chemical_list: D003854:Deoxyribonucleotides; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D013942:Thymine Nucleotides; D000071857:Tumor Suppressor p53-Binding Protein 1; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C024157:thymidine 5'-triphosphate