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      Ubiquitin ligase UBR3 regulates cellular levels of the essential DNA repair protein APE1 and is required for genome stability

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          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.

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          A family of mammalian E3 ubiquitin ligases that contain the UBR box motif and recognize N-degrons.

          Takafumi Tasaki, Lubbertus C F Mulder, Akihiro Iwamatsu … (2005)
          A subset of proteins targeted by the N-end rule pathway bear degradation signals called N-degrons, whose determinants include destabilizing N-terminal residues. Our previous work identified mouse UBR1 and UBR2 as E3 ubiquitin ligases that recognize N-degrons. Such E3s are called N-recognins. We report here that while double-mutant UBR1(-/-) UBR2(-/-) mice die as early embryos, the rescued UBR1(-/-) UBR2(-/-) fibroblasts still retain the N-end rule pathway, albeit of lower activity than that of wild-type fibroblasts. An affinity assay for proteins that bind to destabilizing N-terminal residues has identified, in addition to UBR1 and UBR2, a huge (570 kDa) mouse protein, termed UBR4, and also the 300-kDa UBR5, a previously characterized mammalian E3 known as EDD/hHYD. UBR1, UBR2, UBR4, and UBR5 shared a approximately 70-amino-acid zinc finger-like domain termed the UBR box. The mammalian genome encodes at least seven UBR box-containing proteins, which we propose to call UBR1 to UBR7. UBR1(-/-) UBR2(-/-) fibroblasts that have been made deficient in UBR4 as well (through RNA interference) were significantly impaired in the degradation of N-end rule substrates such as the Sindbis virus RNA polymerase nsP4 (bearing N-terminal Tyr) and the human immunodeficiency virus type 1 integrase (bearing N-terminal Phe). Our results establish the UBR box family as a unique class of E3 proteins that recognize N-degrons or structurally related determinants for ubiquitin-dependent proteolysis and perhaps other processes as well.
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            A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells.

            Jeffrey W H Fung, Bruce Demple (2005)
            Discovered as a DNA repair protein, Ape1 has been associated with other functions, notably redox regulation of transcription factors (Ref1 activity). Because deletion of the mouse gene produces embryonic lethality and stable Ape1-deficient cell lines have not been reported, there has been uncertainty about a possible vital cellular function of Ape1. We addressed this issue by using RNA interference (RNAi) in several human cell types. Strong downregulation of Ape1 stopped cell proliferation and activated apoptosis, which was correlated with accumulation of abasic DNA damage. These effects were reversed by expression of yeast Apn1 protein, which is structurally unrelated to Ape1 but shares enzymatic activity in repair of abasic sites (AP endonuclease). Because Apn1 would lack Ref1 activity or the protein interactions of Ape1, we conclude that the AP endonuclease activity is essential for cellular viability. Accumulation of abasic DNA damage from intrinsic sources appears sufficient to trigger cell death when Ape1-mediated repair is deficient.
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              The intracellular localization of APE1/Ref-1: more than a passive phenomenon?

              Gianluca Tell, Giuseppe Damante, David Caldwell … (2015)
              Human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1) is a perfect paradigm of the functional complexity of a biological macromolecule. First, it plays a crucial role, by both redox-dependent and -independent mechanisms, as a transcriptional coactivator for different transcription factors, either ubiquitous (i.e., AP-1, Egr-1, NF-kappaB, p53, HIF) or tissue-specific (i.e., PEBP-2, Pax-5 and -8, TTF-1), in controlling different cellular processes such as apoptosis, proliferation, and differentiation. Second, it acts, as an apurinic/apyrimidinic endonuclease, during the second step of the DNA base excision repair pathway, which is responsible for the repair of cellular alkylation and oxidative DNA damages. Third, it controls the intracellular reactive oxygen species production by negatively regulating the activity of the Ras-related GTPase Rac1. Despite these known functions of APE1/Ref-1, information is still scanty about the molecular mechanisms responsible for the coordinated control of its several activities. Some evidence suggests that the expression and subcellular localization of APE1/Ref-1 are finely tuned. APE1/Ref-1 is a ubiquitous protein, but its expression pattern differs according to the different cell types. APE1/Ref-1 subcellular localization is mainly nuclear, but cytoplasmic staining has also been reported, the latter being associated with mitochondria and/or presence within the endoplasmic reticulum. It is not by chance that both expression and subcellular localization are altered in several metabolic and proliferative disorders, such as in tumors and aging. Moreover, a fundamental role played by different posttranslational modifications in modulating APE1/Ref-1 functional activity is becoming evident. In the present review, we tried to put together a growing body of information concerning APE1/Ref-1's different functions, shedding new light on present and future directions to understand fully this unique molecule.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nucleic Acids Res
                Journal ID (publisher-id): nar
                Journal ID (hwp): nar
                Title: Nucleic Acids Research
                Publisher: Oxford University Press
                ISSN (Print): 0305-1048
                ISSN (Electronic): 1362-4962
                Publication date Collection: January 2012
                Publication date (Print): January 2012
                Publication date (Electronic): 20 September 2011
                Publication date PMC-release: 20 September 2011
                Volume: 40
                Issue: 2
                Pages: 701-711
                Affiliations
                1Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, 2Biochemistry Department, University of Oxford, Oxfordshire, OX1 3QU, 3Nuffield Department of Clinical Medicine, Centre for Cellular & Molecular Physiology, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK, 4Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA and 5Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 110-799, Korea
                Author notes
                *To whom correspondence should be addressed. Tel: +44 1865617325; Fax: +44 1865617334; Email: grigory.dianov@ 123456rob.ox.ac.uk
                Article
                Publisher ID: gkr744
                DOI: 10.1093/nar/gkr744
                PMC ID: 3258136
                PubMed ID: 21933813
                SO-VID: 4e86eb6e-c1d0-4b5f-be36-4eafdb399d6e
                Copyright © © The Author(s) 2011. Published by Oxford University Press.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 9 February 2011
                Date revision received : 25 August 2011
                Date accepted : 25 August 2011
                Page count
                Pages: 11
                Categories
                Subject: Genome Integrity, Repair and Replication

                ScienceOpen disciplines: Genetics
                Data availability:
                ScienceOpen disciplines: Genetics

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