title: Identification of Fhit as a post-transcriptional effector of Thymidine Kinase 1 expression.
abstract: FHIT is a genome caretaker gene that is silenced in >50% of cancers. Loss of Fhit protein expression promotes accumulation of DNA damage, affects apoptosis and epithelial-mesenchymal transition, though molecular mechanisms underlying these alterations have not been fully elucidated. Initiation of genome instability directly follows Fhit loss and the associated reduced Thymidine Kinase 1 (TK1) protein expression. The effects on TK1 of Fhit knockdown and Fhit induction in the current study confirmed the role of Fhit in regulating TK1 expression. Changes in Fhit expression did not impact TK1 protein turnover or transcription from the TK1 promoter, nor steady-state levels of TK1 mRNA or turnover. Polysome profile analysis showed that up-regulated Fhit expression resulted in decreased TK1 RNA in non-translating messenger ribonucleoproteins and increased ribosome density on TK1 mRNA. Fhit does not bind RNA but its expression increased luciferase expression from a transgene bearing the TK1 5'-UTR. Fhit has been reported to act as a scavenger decapping enzyme, and a similar result with a mutant (H96) that binds but does not cleave nucleoside 5',5'-triphosphates suggests the impact on TK1 translation is due to its ability to modulate the intracellular level of cap-like molecules. Consistent with this, cells expressing Fhit mutants with reduced activity toward cap-like dinucleotides exhibit DNA damage resulting from TK1 deficiency, whereas cells expressing wild-type Fhit or the H96N mutant do not. The results have implications for the mechanism by which Fhit regulates TK1 mRNA, and more broadly, for its modulation of multiple functions as tumor suppressor/genome caretaker.
authors.affiliation: Center for RNA Biology, 484 West 12th Ave., Columbus, OH 43210 USA.|Department of Biological Chemistry and Pharmacology, The Ohio State University, 1060 Carmack Rd., Columbus, OH 43210 USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kiss
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12 Ave., Columbus, OH 43210 USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Waters
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12 Ave., Columbus, OH 43210 USA.|Department of Clinical Pathology, Faculty of Medicine, 2nd floor, Surgery Hospital, Zagazig University, Zagazig 44519, Egypt.
authors.forename: Iman M
authors.initials: IM
authors.lastname: Ouda
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12 Ave., Columbus, OH 43210 USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Saldivar
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12 Ave., Columbus, OH 43210 USA.
authors.forename: Jenna R
authors.initials: JR
authors.lastname: Karras
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12 Ave., Columbus, OH 43210 USA.
authors.forename: Zaynab A
authors.initials: ZA
authors.lastname: Amin
authors.affiliation: Department of Clinical Pathology, Faculty of Medicine, 2nd floor, Surgery Hospital, Zagazig University, Zagazig 44519, Egypt.
authors.forename: Seham
authors.initials: S
authors.lastname: Mahrous
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12 Ave., Columbus, OH 43210 USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Druck
authors.affiliation: Center for RNA Biology, 484 West 12th Ave., Columbus, OH 43210 USA.|Department of Physics, Department of Chemistry and Biochemistry, and Division of Hematology, Department of Internal Medicine, The Ohio State University, 191 West Woodruff Ave., Columbus, OH 43210 USA.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Bundschuh
authors.affiliation: Center for RNA Biology, 484 West 12th Ave., Columbus, OH 43210 USA.|Department of Biological Chemistry and Pharmacology, The Ohio State University, 1060 Carmack Rd., Columbus, OH 43210 USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Schoenberg
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12 Ave., Columbus, OH 43210 USA.
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000235:genetics; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013937:Thymidine Kinase; D000099170:Bis(5'-adenosyl)triphosphatase; C092717:thymidine kinase 1
keywords: 5′-UTR; Fhit; Thymidine kinase 1; Translational control