title: Cell-type specific role of the RNA-binding protein, NONO, in the DNA double-strand break response in the mouse testes.
abstract: The tandem RNA recognition motif protein, NONO, was previously identified as a candidate DNA double-strand break (DSB) repair factor in a biochemical screen for proteins with end-joining stimulatory activity. Subsequent work showed that NONO and its binding partner, SFPQ, have many of the properties expected for bona fide repair factors in cell-based assays. Their contribution to the DNA damage response in intact tissue in vivo has not, however, been demonstrated. Here we compare DNA damage sensitivity in the testes of wild-type mice versus mice bearing a null allele of the NONO homologue (Nonogt). In wild-type mice, NONO protein was present in Sertoli, peritubular myoid, and interstitial cells, with an increase in expression following induction of DNA damage. As expected for the product of an X-linked gene, NONO was not detected in germ cells. The Nonogt/0mice had at most a mild testis developmental phenotype in the absence of genotoxic stress. However, following irradiation at sublethal, 2-4 Gy doses, Nonogt/0mice displayed a number of indicators of radiosensitivity as compared to their wild-type counterparts. These included higher levels of persistent DSB repair foci, increased numbers of apoptotic cells in the seminiferous tubules, and partial degeneration of the blood-testis barrier. There was also an almost complete loss of germ cells at later times following irradiation, evidently arising as an indirect effect reflecting loss of stromal support. Results demonstrate a role for NONO protein in protection against direct and indirect biological effects of ionizing radiation in the whole animal.
authors.affiliation: Departments of Biochemistry and Radiation Oncology, Emory University School of Medicine, 4127 Rollins Research Center,1510 Clifton Rd. NE, Atlanta, GA 30322, USA. Electronic address: shuyi.li2@emory.edu.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Li
authors.affiliation: Departments of Biochemistry and Radiation Oncology, Emory University School of Medicine, 4127 Rollins Research Center,1510 Clifton Rd. NE, Atlanta, GA 30322, USA.
authors.forename: Feng-Jue
authors.initials: FJ
authors.lastname: Shu
authors.affiliation: Departments of Biochemistry and Radiation Oncology, Emory University School of Medicine, 4127 Rollins Research Center,1510 Clifton Rd. NE, Atlanta, GA 30322, USA.
authors.forename: Zhentian
authors.initials: Z
authors.lastname: Li
authors.affiliation: Departments of Biochemistry and Radiation Oncology, Emory University School of Medicine, 4127 Rollins Research Center,1510 Clifton Rd. NE, Atlanta, GA 30322, USA.
authors.forename: Lahcen
authors.initials: L
authors.lastname: Jaafar
authors.affiliation: Columbus Pathology,710 Center Street 101, Columbus, GA 31901, USA.
authors.forename: Shourong
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Departments of Biochemistry and Radiation Oncology, Emory University School of Medicine, 4127 Rollins Research Center,1510 Clifton Rd. NE, Atlanta, GA 30322, USA. Electronic address: wdynan@emory.edu.
authors.forename: William S
authors.initials: WS
authors.lastname: Dynan
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016601:RNA-Binding Proteins; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D013737:Testis / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C500331:Nono protein, mouse; D016601:RNA-Binding Proteins; D004247:DNA
keywords: Double-strand break repair; Ionizing radiation; Knockout mouse; NHEJ; NONO; Testes