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Studies on UAF1-Regulated Deubiquitinase Complexes: USP1/UAF1, USP12/UAF1 and USP46/UAF1

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Studies on UAF1-Regulated Deubiquitinase Complexes: USP1/UAF1, USP12/UAF1 and USP46/UAF1 Studies on UAF1-regulated deubiquitinase complexes: USP1/UAF1, USP12/UAF1 and USP46/UAF1 PhD Thesis Ane Olazabal Herrero 2017 Supervisor: Jose Antonio Rodríguez Pérez (c)2017 ANE OLAZABAL HERRERO Ane Olazabal Herrero is the recipient of a predoctoral fellowship from the University of the Basque Country. She also received financial support for training courses by the COST action (Proteostasis BM1307). This work was supported by the Department of Industry of the Basque Country Government (ETORTEK BioGUNE2010), the Spanish Government MICINN (BFU2009-13,245), and the UPV/EHU (UFI11/20). Table of contents Abbreviations ............................................................................................................................. 1 Abstract ....................................................................................................................................... 5 1. Introduction ........................................................................................................................ 6 1.1. PROTEIN UBIQUITINATION/DEUBIQUITINATION .......................................................... 6 1.2. HUMAN DEUBIQUITINATING ENZYMES (DUBs) .......................................................... 10 1.2.1. Cellular functions of DUBs ................................................................................... 10 1.2.2. Domain architecture and classification of DUBs ................................................. 11 1.3. THE USP SUBFAMILY OF DUBs .................................................................................... 12 1.3.1. General structural features and ubiquitin chain specificity of USPs ................... 12 1.3.2. Regulation of USP catalytic activity ..................................................................... 14 1.4. WDR48/UAF1, AN ACTIVATING COFACTOR OF USP1, USP12 AND USP46 ................. 15 1.4.1. UAF1 domain structure ....................................................................................... 15 1.4.2. UAF1 function ...................................................................................................... 16 1.5. THE USP1/UAF1 DEUBIQUITINASE COMPLEX ............................................................. 17 1.5.1. Domain structure and functional motifs in USP1 ................................................ 17 1.5.2. The role of the USP1/UAF1 complex in the response to DNA damage .............. 18 1.5.3. Regulation of the USP1/UAF1 complex ............................................................... 22 1.5.4. USP1 alterations in cancer .................................................................................. 25 1.5.5. The USP1/UAF1 complex as a therapeutic target in cancer ............................... 26 1.6. THE USP12/UAF1 AND USP46/UAF1 DEUBIQUITINASE COMPLEXES ......................... 27 1.6.1. Domain structure and functional motifs of USP12 and USP46 ........................... 27 1.6.2. Cellular functions of the USP12 and USP46 ........................................................ 28 1.6.3. Regulation of USP12 and USP46 by UAF1 and WDR20 ....................................... 29 2. Hypotheses and aims ...................................................................................................... 32 3. Materials and Methods................................................................................................... 34 3.1. BIOINFORMATICS TOOLS ............................................................................................ 34 3.1.1. Sequence alignment and 3D structure modeling ................................................ 34 3.1.2. COSMIC mutation database ................................................................................ 34 3.2. CLONING AND MUTAGENESIS ..................................................................................... 34 3.2.1. “Classical”-restriction enzyme-based cloning ..................................................... 35 3.2.2. Gibson assembly cloning ..................................................................................... 37 3.2.3. Site-directed mutagenesis ................................................................................... 39 3.2.4. Plasmid isolation and DNA sequencing ............................................................... 40 3.3. CELL CULTURE ............................................................................................................. 41 3.3.1. Cell lines and cell culture conditions ................................................................... 41 3.3.2. Cell seeding ......................................................................................................... 41 3.3.3. Transfection ......................................................................................................... 42 3.3.4. Drug treatments .................................................................................................. 44 3.3.5. Sulforhodamine B (SRB) cell viability assay ......................................................... 44 3.4. FLUORESCENCE MICROSCOPY TECHNIQUES............................................................... 46 3.4.1. Immunofluorescence .......................................................................................... 46 3.4.2. Live cell microscopy ............................................................................................. 47 3.4.3. Microscopes ........................................................................................................ 47 3.4.4. Image analysis for quantification of FK2 fluorescence and 53BP1 foci .............. 48 3.5. TECHNIQUES FOR RNA ANALYSIS ................................................................................ 48 3.5.1. RNA isolation ....................................................................................................... 48 3.5.2. cDNA synthesis .................................................................................................... 49 3.5.3. qRT-PCR ............................................................................................................... 49 3.5.4. Analysis of DNA adducts using quantitative extra-long PCR (XL-PCR) and Taqman assays…………… ..................................................................................................................... 49 3.6. TECHNIQUES FOR PROTEIN ANALYSIS ........................................................................ 50 3.6.1. Protein extraction................................................................................................ 50 3.6.2. Protein quantification ......................................................................................... 51 3.6.3. Immunoprecipitation using GFP-trap magnetic beads ....................................... 52 3.6.4. Immunoblot ......................................................................................................... 52 3.7. PULLDOWN OF ENDOGENOUS UBIQUITINATED PROTEINS USING bioUb ........................ 54 3.7.1. The bioUb strategy .............................................................................................. 54 3.7.2. bioUb protocol: preparation of cell extracts and purification of biotinylated proteins…............................................................................................................................. 56 3.7.3. Silver staining ...................................................................................................... 58 3.8. IDENTIFICATION OF bioUb-ENRICHED ENDOGENOUS UBIQUITINATED PROTEINS USING MASS SPECTROMETRY ................................................................................................. 58 3.8.1. General aspects of mass spectrometry ............................................................... 58 3.8.2. In-gel trypsin digestion and peptide extraction .................................................. 59 3.8.3. Liquid chromatography (LC)-MS/MS analysis ..................................................... 60 3.8.4. Data processing and bioinformatics analysis ...................................................... 61 3.9. SUPPLEMENTARY MATERIALS AND METHODS ........................................................... 62 3.9.1. PCR reactions and programs ............................................................................... 62 3.9.2. Solutions .............................................................................................................. 64 4. Results ................................................................................................................................ 67 4.1. INSIGHTS INTO THE REGULATION OF USP1 BY PHOSPHORYLATION AND AUTOCLEAVAGE ...................................................................................................................... 67 4.1.1. Phosphorylation of USP1 at serine 313 is dispensable for the formation and activity of USP1/UAF1 complex ........................................................................................... 67 4.1.2. USP1 autocleavage at the G670/G671 diglycine motif occurs most likely in cis……………………………………………………………………………………………………………………………………71 4.2. CONFIRMATION AND FINE MAPPING OF THE USP1/UAF1 INTERACTION INTERFACE ……………………………………………………………………………………………………………………………….74 4.2.1. Side-by-side comparison of the two reported UAF1-binding sites in USP1........ 74 4.2.2. The "Fingers" subdomain is the UAF1-binding site in USP1 ...............................78 4.2.3. Fine-mapping of the UAF1/USP1 interaction.....................................................
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