title: Ccdc94 protects cells from ionizing radiation by inhibiting the expression of p53.
abstract: DNA double-strand breaks (DSBs) represent one of the most deleterious forms of DNA damage to a cell. In cancer therapy, induction of cell death by DNA DSBs by ionizing radiation (IR) and certain chemotherapies is thought to mediate the successful elimination of cancer cells. However, cancer cells often evolve to evade the cytotoxicity induced by DNA DSBs, thereby forming the basis for treatment resistance. As such, a better understanding of the DSB DNA damage response (DSB-DDR) pathway will facilitate the design of more effective strategies to overcome chemo- and radioresistance. To identify novel mechanisms that protect cells from the cytotoxic effects of DNA DSBs, we performed a forward genetic screen in zebrafish for recessive mutations that enhance the IR-induced apoptotic response. Here, we describe radiosensitizing mutation 7 (rs7), which causes a severe sensitivity of zebrafish embryonic neurons to IR-induced apoptosis and is required for the proper development of the central nervous system. The rs7 mutation disrupts the coding sequence of ccdc94, a highly conserved gene that has no previous links to the DSB-DDR pathway. We demonstrate that Ccdc94 is a functional member of the Prp19 complex and that genetic knockdown of core members of this complex causes increased sensitivity to IR-induced apoptosis. We further show that Ccdc94 and the Prp19 complex protect cells from IR-induced apoptosis by repressing the expression of p53 mRNA. In summary, we have identified a new gene regulating a dosage-sensitive response to DNA DSBs during embryonic development. Future studies in human cancer cells will determine whether pharmacological inactivation of CCDC94 reduces the threshold of the cancer cell apoptotic response.
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Shelly
authors.initials: S
authors.lastname: Sorrells
authors.forename: Seth
authors.initials: S
authors.lastname: Carbonneau
authors.forename: Erik
authors.initials: E
authors.lastname: Harrington
authors.forename: Aye T
authors.initials: AT
authors.lastname: Chen
authors.forename: Bridgid
authors.initials: B
authors.lastname: Hast
authors.forename: Brett
authors.initials: B
authors.lastname: Milash
authors.forename: Ujwal
authors.initials: U
authors.lastname: Pyati
authors.forename: Michael B
authors.initials: MB
authors.lastname: Major
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Stewart
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Cicely
authors.initials: C
authors.lastname: Jette
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D047108:Embryonic Development / Q000528:radiation effects; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D009154:Mutation; D009474:Neurons / Q000528:radiation effects; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C571228:tp53 protein, zebrafish; C577065:yju2 protein, zebrafish