title: Treacher Collins syndrome TCOF1 protein cooperates with NBS1 in the DNA damage response.
abstract: The signal transduction pathway of the DNA damage response (DDR) is activated to maintain genomic integrity following DNA damage. The DDR promotes genomic integrity by regulating a large network of cellular activities that range from DNA replication and repair to transcription, RNA splicing, and metabolism. In this study we define an interaction between the DDR factor NBS1 and TCOF1, a nucleolar protein that regulates ribosomal DNA (rDNA) transcription and is mutated in Treacher Collins syndrome. We show that NBS1 relocalizes to nucleoli after DNA damage in a manner dependent on TCOF1 and on casein kinase II and ATM, which are known to modify TCOF1 by phosphorylation. Moreover, we identify a putative ATM phosphorylation site that is required for NBS1 relocalization to nucleoli in response to DNA damage. Last, we report that TCOF1 promotes cellular resistance to DNA damaging agents. Collectively, our findings identify TCOF1 as a DDR factor that could cooperate with ATM and NBS1 to suppress inappropriate rDNA transcription and maintain genomic integrity after DNA damage.
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115; Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032; and selledge@genetics.med.harvard.edu ac3685@columbia.edu.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ciccia
authors.affiliation: Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032; and.
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115;
authors.forename: Lior
authors.initials: L
authors.lastname: Izhar
authors.affiliation: Department of Cell Biology, Harvard University Medical School, Boston, MA 02115.
authors.forename: Mathew E
authors.initials: ME
authors.lastname: Sowa
authors.affiliation: Department of Cell Biology, Harvard University Medical School, Boston, MA 02115.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115; selledge@genetics.med.harvard.edu ac3685@columbia.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004275:DNA, Ribosomal / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004275:DNA, Ribosomal; C112156:NBN protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; C105442:TCOF1 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; CK2; DNA damage response; nucleolus; protein phosphorylation