title: Circadian clock disruption improves the efficacy of chemotherapy through p73-mediated apoptosis.
abstract: The circadian clock in mammalian organisms is generated by a transcription-translation feedback loop that controls many biochemical pathways at the cellular level and physiology and behavior at the organismal level. Cryptochrome (Cry) is a key protein in the negative arm of the transcription-translation feedback loop. It has been found that Cry mutation in cells with p53-null genotype increased their sensitivity to apoptosis by genotoxic agents. Here we show that this increased sensitivity is due to up-regulation of the p53 gene family member p73 in response to DNA damage. As a consequence, when tumors arising from oncogenic Ras-transformed p53(-/-) and p53(-/-)Cry1(-/-)Cry2(-/-) cells are treated with the anticancer drug oxaliplatin, p53(-/-) tumors continue to grow whereas p53(-/-)Cry1(-/-)Cry2(-/-) tumors exhibit extensive apoptosis and stop growing. This finding provides a mechanistic foundation for overcoming the resistance of p53-deficient tumor cells to apoptosis induced by DNA-damaging agents and suggests that disruption of cryptochrome function may increase the sensitivity of tumors with p53 mutation to chemotherapy.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Jin Hyup
authors.initials: JH
authors.lastname: Lee
authors.forename: Aziz
authors.initials: A
authors.lastname: Sancar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D057906:Circadian Clocks / Q000235:genetics*; D056931:Cryptochromes / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D009369:Neoplasms / Q000473:pathology*; D009687:Nuclear Proteins / Q000502:physiology*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D049268:Positron-Emission Tomography / Q000379:methods; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D056931:Cryptochromes; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000077150:Oxaliplatin