title: USP47 is a deubiquitylating enzyme that regulates base excision repair by controlling steady-state levels of DNA polymerase β.
abstract: DNA base excision repair (BER) is an essential cellular process required for genome stability, and misregulation of BER is linked to premature aging, increased rate of mutagenesis, and cancer. We have now identified the cytoplasmic ubiquitin-specific protease USP47 as the major enzyme involved in deubiquitylation of the key BER DNA polymerase (Pol β) and demonstrate that USP47 is required for stability of newly synthesized cytoplasmic Pol β that is used as a source for nuclear Pol β involved in DNA repair. We further show that knockdown of USP47 causes an increased level of ubiquitylated Pol β, decreased levels of Pol β, and a subsequent deficiency in BER, leading to accumulation of DNA strand breaks and decreased cell viability in response to DNA damage. Taken together, these data demonstrate an important role for USP47 in regulating DNA repair and maintaining genome integrity.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Parsons
authors.forename: Irina I
authors.initials: II
authors.lastname: Dianova
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Khoronenkova
authors.forename: Mariola J
authors.initials: MJ
authors.lastname: Edelmann
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.forename: Grigory L
authors.initials: GL
authors.lastname: Dianov
mesh_terms: D020134:Catalytic Domain; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000378:metabolism*; D004260:DNA Repair; D015971:Gene Expression Regulation, Enzymologic; D016678:Genome; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008954:Models, Biological; D025801:Ubiquitin / Q000737:chemistry*; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000502:physiology*; D064570:Ubiquitin-Specific Proteases
chemical_list: C557800:USP47 protein, human; D025801:Ubiquitin; D019951:DNA Polymerase beta; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; D008239:Lysine