title: ZNF281 contributes to the DNA damage response by controlling the expression of XRCC2 and XRCC4.
abstract: ZNF281 is a zinc-finger factor involved in the control of cellular stemness and epithelial-mesenchymal transition (EMT). Here, we report that ZNF281 expression increased after genotoxic stress caused by DNA-damaging drugs. Comet assays demonstrated that DNA repair was delayed in cells silenced for the expression of ZNF281 and treated with etoposide. Furthermore, the expression of 10 DNA damage response genes was downregulated in cells treated with etoposide and silenced for ZNF281. In line with this finding, XRCC2 and XRCC4, two genes that take part in homologous recombination and non-homologous end joining, respectively, were transcriptionally activated by ZNF281 through a DNA-binding-dependent mechanism, as demonstrated by luciferase assays and Chromatin crosslinking ImmunoPrecipitation experiments. c-Myc, which also binds to the promoters of XRCC2 and XRCC4, was unable to promote their transcription or to modify ZNF281 activity. Of interest, bioinformatic analysis of 1971 breast cancer patients disclosed a significant correlation between the expression of ZNF281 and that of XRCC2. In summary, our data highlight, for the first time, the involvement of ZNF281 in the cellular response to genotoxic stress through the control exercised on the expression of genes that act in different repair mechanisms.
authors: Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.
authors: M
authors: M
authors: Pieraccioli
authors: Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.
authors: S
authors: S
authors: Nicolai
authors: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors: A
authors: A
authors: Antonov
authors: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors: J
authors: J
authors: Somers
authors: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors: M
authors: M
authors: Malewicz
authors: Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.|Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors: G
authors: G
authors: Melino
authors: Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.|Radiation Biology and Human Health Unit, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA) Research Center Casaccia, Rome, Italy.
authors: G
authors: G
authors: Raschellà
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D012097:Repressor Proteins; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000097796:Nucleolin
chemical_list: D056744:Cyclin B1; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D000097796:Nucleolin; C113187:XRCC2 protein, human; C101467:XRCC4 protein, human; C120370:ZNF281 protein, human