Ubiquitin-binding domains and their role in the DNA damage response |
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| Authors: | Kay Hofmann |
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| Institution: | 1. Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK;2. Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK;3. TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK;4. Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, Ofra s/n, 38320 La Laguna, Tenerife, Spain;5. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia;6. Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia;1. MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK;1. Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK;1. Department of Radiology, The Ohio State University, Columbus, OH, 43210, United States;2. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, 43210, United States;3. James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, 43210, United States;1. Department of Microbiology and Molecular Genetics, University of California, Davis, CA 95616, USA;2. Department of Molecular and Cellular Biology, University of California, Davis, CA 95616, USA;3. Spatial Regulation of Genomes, Department of Genomes and Genetics, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 3525, Institut Pasteur, 75015 Paris, France;1. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA;2. Howard Hughes Medical Institute, Berkeley, CA, USA;3. Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA;4. Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA, USA;5. Department of Microchemistry, Proteomics, and Lipidomics, Genentech Inc., South San Francisco, CA, USA;6. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA;7. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA |
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| Abstract: | The modification of eukaryotic proteins by covalent attachment of ubiquitin is a versatile signaling event with a wide range of possible consequences. Canonical poly-ubiquitination by Lys-48 linked chains usually destines a protein for degradation by the proteasome. By contrast, attachment of a single ubiquitin or ubiquitin chains linked through Lys-63 or Lys-6 serves a non-proteolytic role. Over the last years, evidence has accumulated that several nuclear proteins become ubiquitinated in response to DNA damage. Typically, these proteins carry mono-ubiquitin or non-classical ubiquitin chains and are localized close to the site of DNA damage. Of particular interest are PCNA and the variant histone H2AX, two key proteins whose ubiquitination serves to recruit factors needed by the cell to cope with the damage. A prerequisite for docking effector proteins to the site of the lesion is the detection of a specific ubiquitin modification, a process that can be mediated by a range of dedicated ubiquitin-binding domains (UBDs). As the same types of ubiquitin modification are involved in entirely different processes, the recognition of the ubiquitin mark has to go along with the recognition of the modified protein. Thus, ubiquitin-binding domains gain their specificity through combination with other recognition domains and motifs. This review discusses ubiquitin-binding domains relevant to the DNA damage response, including their binding mode, their specificity, and their interdependence with other factors. For several repair pathways, current knowledge of the events downstream of the ubiquitin mark is sketchy. A closer look at orphan UBD proteins might lead to the identification of missing pieces in the DNA response puzzle. |
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