title: TOPBP1Dpb11plays a conserved role in homologous recombination DNA repair through the coordinated recruitment of 53BP1Rad9.
abstract: Genome maintenance and cancer suppression require homologous recombination (HR) DNA repair. In yeast and mammals, the scaffold protein TOPBP1Dpb11has been implicated in HR, although its precise function and mechanism of action remain elusive. In this study, we show that yeast Dpb11 plays an antagonistic role in recombination control through regulated protein interactions. Dpb11 mediates opposing roles in DNA end resection by coordinating both the stabilization and exclusion of Rad9 from DNA lesions. The Mec1 kinase promotes the pro-resection function of Dpb11 by mediating its interaction with the Slx4 scaffold. Human TOPBP1Dpb11engages in interactions with the anti-resection factor 53BP1 and the pro-resection factor BRCA1, suggesting that TOPBP1 also mediates opposing functions in HR control. Hyperstabilization of the 53BP1-TOPBP1 interaction enhances the recruitment of 53BP1 to nuclear foci in the S phase, resulting in impaired HR and the accumulation of chromosomal aberrations. Our results support a model in which TOPBP1Dpb11plays a conserved role in mediating a phosphoregulated circuitry for the control of recombinational DNA repair.
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Yi
authors.identifier: 0000-0003-2564-8965
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
authors.forename: José Renato
authors.identifier: 0000-0001-5909-8215
authors.initials: JR
authors.lastname: Cussiol
authors.affiliation: Department of Biosciences, University of Milan, 20133 Milan, Italy.
authors.forename: Diego
authors.identifier: 0000-0002-9549-5258
authors.initials: D
authors.lastname: Dibitetto
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Jennie Rae
authors.initials: JR
authors.lastname: Sims
authors.affiliation: Department of Biosciences, University of Milan, 20133 Milan, Italy.
authors.forename: Shyam
authors.identifier: 0000-0002-0220-5910
authors.initials: S
authors.lastname: Twayana
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Robert Samuel
authors.identifier: 0000-0003-3327-1379
authors.initials: RS
authors.lastname: Weiss
authors.affiliation: Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologias Biomedicas, 38320 Tenerife, Spain.
authors.forename: Raimundo
authors.initials: R
authors.lastname: Freire
authors.affiliation: Department of Biosciences, University of Milan, 20133 Milan, Italy.
authors.forename: Federica
authors.identifier: 0000-0002-9495-2349
authors.initials: F
authors.lastname: Marini
authors.affiliation: Department of Biosciences, University of Milan, 20133 Milan, Italy.
authors.forename: Achille
authors.identifier: 0000-0002-1528-9009
authors.initials: A
authors.lastname: Pellicioli
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853 mbs266@cornell.edu.
authors.forename: Marcus Bustamante
authors.identifier: 0000-0001-9952-2885
authors.initials: MB
authors.lastname: Smolka
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005656:Fungal Proteins / Q000235:genetics; D057809:HEK293 Cells; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D059767:Recombinational DNA Repair / Q000235:genetics*; D016196:S Phase / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics*; D015003:Yeasts
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D009687:Nuclear Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1