title: A genome-wide IR-induced RAD51 foci RNAi screen identifies CDC73 involved in chromatin remodeling for DNA repair.
abstract: To identify new regulators of homologous recombination repair, we carried out a genome-wide short-interfering RNA screen combined with ionizing irradiation using RAD51 foci formation as readout. All candidates were confirmed by independent short-interfering RNAs and validated in secondary assays like recombination repair activity and RPA foci formation. Network analysis of the top modifiers identified gene clusters involved in recombination repair as well as components of the ribosome, the proteasome and the spliceosome, which are known to be required for effective DNA repair. We identified and characterized the RNA polymerase II-associated protein CDC73/Parafibromin as a new player in recombination repair and show that it is critical for genomic stability. CDC73 interacts with components of the SCF/Cullin and INO80/NuA4 chromatin-remodeling complexes to promote Histone ubiquitination. Our findings indicate that CDC73 is involved in local chromatin decondensation at sites of DNA damage to promote DNA repair. This function of CDC73 is related to but independent of its role in transcriptional elongation.
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Herr
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lundin
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Evers
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford , Headington, UK.
authors.forename: Daniel
authors.identifier: 0000-0002-6495-7026
authors.initials: D
authors.lastname: Ebner
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford , Headington, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Bauerschmidt
authors.affiliation: CR-UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford , Oxford, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Kingham
authors.affiliation: School of Life Sciences, University of Lincoln, Brayford Pool , Lincoln, UK.
authors.forename: Timea
authors.identifier: 0000-0002-7402-2144
authors.initials: T
authors.lastname: Palmai-Pallag
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mortusewicz
authors.affiliation: Science for Life Laboratory, Bioinformatics Centre Stockholm, Department of Biochemistry and Biophysics, Stockholm University , Stockholm, Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Frings
authors.affiliation: Science for Life Laboratory, Bioinformatics Centre Stockholm, Department of Biochemistry and Biophysics, Stockholm University , Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Sonnhammer
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
keywords: CDC73; DNA repair; Parafibromin; RAD51; chromatin remodeling; genome-wide siRNA screen; homologous recombination; tumor suppressor