title: DNA damage-specific control of cell death by cryptochrome in p53-mutant ras-transformed cells.
abstract: The main feedback loop driving circadian rhythm in mice is controlled, in part, by the genes encoding the cryptochromes Cry1 and Cry2. Targeted mutation of both Cry1 and Cry2 delay the early onset of tumor formation in p53-null mutant mice. Furthermore, Ras-transformed p53- and Cry-null mouse skin fibroblasts are more sensitive than p53 mutants to apoptotic cell death initiated by agents that activate either the intrinsic or the extrinsic apoptosis pathways. Here, we investigated the effect of Cry1 and Cry2 mutations on cell death by other genotoxic agents that generate alkylated bases, interstrand crosslinks, DNA-protein crosslinks, and double-strand breaks. Both ultraviolet (UV) and the UV mimetic compound oxaliplatin and the radiomimetic compound doxorubicin promoted apoptosis by upregulating the tumor suppressor p73. However, only the UV and oxaliplatin-induced upregulation of p73 mediated by the transcription factor Egr1, but not the doxorubicin-induced upregulation mediated by the transcription factor E2F1, was enhanced by Cry1/Cry2 double mutation. Accordingly, Egr1 downregulation reduced oxaliplatin-induced apoptosis, whereas E2F1 downregulation reduced doxorubicin-induced apoptosis. Our findings establish distinct roles for cryptochromes in intrinsic apoptosis induced by UV mimetic and radiomimetic agents.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Jin Hyup
authors.initials: JH
authors.lastname: Lee
authors.forename: Shobhan
authors.initials: S
authors.lastname: Gaddameedhi
authors.forename: Nuri
authors.initials: N
authors.lastname: Ozturk
authors.forename: Rui
authors.initials: R
authors.lastname: Ye
authors.forename: Aziz
authors.initials: A
authors.lastname: Sancar
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D056931:Cryptochromes / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D004317:Doxorubicin / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: C538963:CRY1 protein, human; C538966:CRY2 protein, human; D056931:Cryptochromes; D004268:DNA-Binding Proteins; D009153:Mutagens; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000077150:Oxaliplatin; D004317:Doxorubicin