title: Analysis of mutant frequencies and mutation spectra in hMTH1 knockdown TK6 cells exposed to UV radiation.
abstract: Ultraviolet radiation is a highly mutagenic agent that damages the DNA by the formation of mutagenic photoproducts at dipyrimidine sites and by oxidative DNA damages via reactive oxygen species (ROS). ROS can also give rise to mutations via oxidation of dNTPs in the nucleotide pool, e.g. 8-oxo-dGTP and 2-OH-dATP and subsequent incorporation during DNA replication. Here we show that expression of human MutT homolog 1 (hMTH1) which sanitizes the nucleotide pool by dephosphorylating oxidized dNTPs, protects against mutagenesis induced by long wave UVA light and by UVB light but not by short wave UVC light. Mutational spectra analyses of UVA-induced mutations at the endogenous Thymidine kinase gene in human lymphoblastoid cells revealed that hMTH1 mainly protects cells from transitions at GC and AT base pairs.
authors.affiliation: Center for Radiation Protection Research, Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Sweden.
authors.forename: Asal
authors.initials: A
authors.lastname: Fotouhi
authors.forename: Winta Woldai
authors.initials: WW
authors.lastname: Hagos
authors.forename: Marina
authors.initials: M
authors.lastname: Ilic
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wojcik
authors.forename: Mats
authors.initials: M
authors.lastname: Harms-Ringdahl
authors.forename: Frank
authors.initials: F
authors.lastname: de Gruijl
authors.forename: Leon
authors.initials: L
authors.lastname: Mullenders
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Jansen
authors.forename: Siamak
authors.initials: S
authors.lastname: Haghdoost
mesh_terms: D020029:Base Pairing / Q000528:radiation effects; D002460:Cell Line; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D016296:Mutagenesis / Q000528:radiation effects; D009154:Mutation / Q000528:radiation effects*; D059645:Mutation Rate; D009711:Nucleotides / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: D009711:Nucleotides; D013937:Thymidine Kinase; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes
keywords: 2-OH-dA; 2-OH-dATP; 2-hydroxydeoxyadenosine; 2-hydroxydeoxyadenosine 5′-triphosphate; 6-4PP; 8-Oxo-dG; 8-oxo-2′-deoxyguanosine; 8-oxo-2′-deoxyguanosine-5′-triphosphate; 8-oxo-dG; 8-oxo-dGTP; CPD; KD; Nucleotide pool; Oxidative stress; ROS; TFT; TK6; Thymidine kinase; Tk; UVR; Ultraviolet radiation; WT; cyclobutane pyrimidine dimer; dNTP; deoxyribonucleotide triphosphate; hMTH1; human B lymphoblastoid cells; human MutT homolog protein; knockdown; pyrimidine (6-4) pyrimidone photoproduct; reactive oxygen species; trifluorothymidine; ultraviolet radiation; wildtype