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FLASH GENE
Symbol WDR48 contributors: mct/npt/pgu - updated : 27-12-2018
HGNC name WD repeat domain 48
HGNC id 30914
Corresponding disease
SPG60 spastic paraplegia 60
Location 3p22.2      Physical location : 39.093.506 - 39.137.879
Synonym name
  • USP1 associated factor 1
  • WD repeat endosomal protein
  • Synonym symbol(s) P80, KIAA1449, DKFZp686G1794, UAF1
    DNA
    TYPE functioning gene
    STRUCTURE 44.37 kb     19 Exon(s)
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    19 - 3705 76 677 - 2009 19075014
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunethymus   highly
    Nervousbrainbasal nucleicorpus callosum highly
     brainbasal nucleicaudate nucleus highly
     brainmidbrainsubstantia nigra moderately
     braindiencephalonthalamusnucleihighly
    Reproductivefemale systemovary  highly
     female systemuteruscervix moderately
     male systemtestis  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • seven WD repeats
  • a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2), with SLD2 that binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI and C-terminal SUMO-like domain encircling the USP46-bound ubiquitin
  • a novel ancillary domain
  • HOMOLOGY
    Homologene
    FAMILY
  • WD repeat WDR48 family
  • CATEGORY transport
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,lysosome
    intracellular,nucleus
    text
  • USP12/WDR48/WDR20 complex dynamically shuttles between the plasma membrane, cytoplasm and nucleus
  • basic FUNCTION
  • involved in protein transport
  • activating FANCD2, through formation of a stable USP1/WDR48 protein complex
  • functions as an activator of USP1
  • stimulates the catalytic activities of USP1, USP12, and USP46
  • FANCD2-Ub and PCNA-Ub
  • USP1/WDR48 complex promotes homologous recombination, at least in part by suppressing nonhomologous end-joining
  • USP1/WDR48 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair
  • USP12 and WDR48 regulate deubiquitination of nonactivated NOTCH1
  • potential importance of the USP12/WDR48/WDR20 complex in AR regulation and prostate cancer progression
  • docks at the distal end of the USP12 fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft
  • is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • formation of a stable USP1/WDR48 protein complex, activating FANCD2 , and can deubiquitinate PCNA
  • part of USP12·WDR48·WDR20 complex (potentially involved in other types of transcriptional regulation)
  • USP1/WDR48 complex is a regulator of the cellular response to DNA damage
  • similar to PHLPP1 function, WDR48 and USP12 negatively regulate AKT1 activation and thus promote cellular apoptosis
  • USP1/WDR48 complex promotes stem cell conservation and regulation of DNA damage repair
  • USP1-WDR48 complex is a potential target for the prevention of viral diseases
  • USP12/WDR48/WDR20 complex dynamically shuttles between the plasma membrane, cytoplasm and nucleus
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with WDR20 (WDR20, a WD40-repeat containing protein, is a common binding partner of WDR48, USP12, and USP46)
  • binds and stimulates three deubiquitinating enzymes: USP1, USP12, and USP46
  • ATAD5 specifically directs USP1-WDR48 complex for PCNA deubiquitination
  • serine phosphorylation is critical for the activation of USP1 and its interaction with WDR48
  • important regulatory role of the USP1-WDR48 complex in HR (homologous recombination) repair through its regulation of the FANCD2-ubiquitinated (Ub) and PCNA-Ub cellular pools
  • USP12, in complex with WDR48 and WDR20, deubiquitinates the AR to enhance receptor stability and transcriptional activity
  • WDR48 and USP12 are novel PHLPP1 regulators and potential suppressors of tumor cell survival
  • USP1 amino acid motif 420-520 is necessary and sufficient for WDR48 binding
  • WDR48 interacts with the USP46 fingers subdomain via a relatively small, highly polar surface on the top center of the WDR48 beta propeller
  • USP12 is known to require the co-factors WDR48 and WDR20 for catalytic activity
  • efficient USP1 activity requires binding to its cofactor USP1-associated factor 1 (WDR48), and the USP1-WDR48 deubiquitinase complex has important roles in regulating DNA damage-related processes
  • WDR48 and WDR20 interact with USP12 at two distinct sites far from its catalytic center
  • USP1-WDR48 complex promotes homologous recombination (HR) repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1
  • USP46 is regulated by two WD40-repeat (WDR) proteins, WDR48/UAF1 and WDR20
  • mechanistically, USP1 and WDR48 bound to TBK1, removed its K48-linked polyubiquitination, and then reversed the degradation process of TBK1
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) SPG60
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductiveprostate
    USP12 interacting partners WDR48 and WDR20 are potential therapeutic targets in prostate cancer
    ANIMAL & CELL MODELS
  • Uaf1 deficiency in mice led to increased levels of cellular Fancd2-Ub and Pcna-Ub