title: Ubiquitin ligase UBR3 regulates cellular levels of the essential DNA repair protein APE1 and is required for genome stability.
abstract: APE1 (Ref-1) is an essential human protein involved in DNA damage repair and regulation of transcription. Although the cellular functions and biochemical properties of APE1 are well characterized, the mechanism involved in regulation of the cellular levels of this important DNA repair/transcriptional regulation enzyme, remains poorly understood. Using an in vitro ubiquitylation assay, we have now purified the human E3 ubiquitin ligase UBR3 as a major activity that polyubiquitylates APE1 at multiple lysine residues clustered on the N-terminal tail. We further show that a knockout of the Ubr3 gene in mouse embryonic fibroblasts leads to an up-regulation of the cellular levels of APE1 protein and subsequent genomic instability. These data propose an important role for UBR3 in the control of the steady state levels of APE1 and consequently error free DNA repair.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Meisenberg
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Tait
authors.forename: Irina I
authors.initials: II
authors.lastname: Dianova
authors.forename: Katherine
authors.initials: K
authors.lastname: Wright
authors.forename: Mariola J
authors.initials: MJ
authors.lastname: Edelmann
authors.forename: Nicola
authors.initials: N
authors.lastname: Ternette
authors.forename: Takafumi
authors.initials: T
authors.lastname: Tasaki
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.forename: Jason L
authors.initials: JL
authors.lastname: Parsons
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
authors.forename: Grigory L
authors.initials: GL
authors.lastname: Dianov
mesh_terms: D000818:Animals; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000378:metabolism*; D055786:Gene Knockout Techniques; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C522185:UBR3 protein, mouse; D044767:Ubiquitin-Protein Ligases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D008239:Lysine