title: Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and senescence caused by C-MYC depletion.
abstract: The down-regulation of dominant oncogenes, including C-MYC, in tumor cells often leads to the induction of senescence via mechanisms that are not completely identified. In the current study, we demonstrate that MYC-depleted melanoma cells undergo extensive DNA damage that is caused by the underexpression of thymidylate synthase (TS) and ribonucleotide reductase (RR) and subsequent depletion of deoxyribonucleoside triphosphate pools. Simultaneous genetic inhibition of TS and RR in melanoma cells induced DNA damage and senescence phenotypes very similar to the ones caused by MYC-depletion. Reciprocally, overexpression of TS and RR in melanoma cells or addition of deoxyribo-nucleosides to culture media substantially inhibited DNA damage and senescence-associated phenotypes caused by C-MYC depletion. Our data demonstrate the essential role of TS and RR in C-MYC-dependent suppression of senescence in melanoma cells.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Mannava
authors.forename: Kalyana C
authors.initials: KC
authors.lastname: Moparthy
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Wheeler
authors.forename: Katerina I
authors.initials: KI
authors.lastname: Leonova
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Wawrzyniak
authors.forename: Anna
authors.initials: A
authors.lastname: Bianchi-Smiraglia
authors.forename: Albert E
authors.initials: AE
authors.lastname: Berman
authors.forename: Sheryl
authors.initials: S
authors.lastname: Flanagan
authors.forename: Donna S
authors.initials: DS
authors.lastname: Shewach
authors.forename: Nathalie C
authors.initials: NC
authors.lastname: Zeitouni
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Mathews
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Nikiforov
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D003853:Deoxyribonucleosides / Q000494:pharmacology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012262:Ribonucleoside Diphosphate Reductase / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D003853:Deoxyribonucleosides; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; D012264:Ribonucleotide Reductases; C093713:ribonucleotide reductase M2; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D013940:Thymidylate Synthase