WDR48 (WD repeat domain 48)
2017-04-01 Anne Olazabal-Herrero , Godefridus J Peters , Elisa Giovannetti , Jose Antonio Rodriguez AffiliationIdentity
HGNC
LOCATION
3p22.2 (Starts at 39051986 and ends at 39096671 bp from pter (according to hg-38))
IMAGE
LEGEND
Figure 1: Localization of WDR48 on chromosome 3p22.2. WDR48 starts from 39051986 and ends at 39096671 bp.
LOCUSID
ALIAS
Bun62,P80,SPG60,UAF1
FUSION GENES
Abstract
WDR48 is a WD40-repeat containing protein that regulates the activity of three human deubiquitinating enzymes: USP1, USP12 and USP46. The best characterized role of WDR48 is regulation of the DNA damage response in complex with USP1. The USP1\/WDR48 complex promotes deubiquitination of monoubiquitinated FANCD2 and monoubiquitinated PCNA, which are required in the regulation of translesion synthesis (TLS) and Fanconi anemia (FA) DNA repair pathways, respectively. In addition, in complex with USP12 and USP46, WDR48 regulates other important cellular processes such as synaptic transmission or signalling through the Akt, Notch and T-cell receptor pathways.
DNA/RNA
Description
WDR48 gene is located on chromosome 3 in the region p22.2. WDR48 was first cloned in 2000 (Nagase et al., 2000) as a gene coding for a 607 amino acid protein called KIAA1449. In 2002, Park and co-workers (Park et al., 2002) cloned the full-length cDNA encoding the 677 amino acid WDR48 protein, which they called p80.
Transcription
Ten alternatively spliced transcript variants have been identified (WDR48-001, -003, -004, -005, -006, -007, -008, -009, -010 and -011) for this gene. Transcription variants -001 and -008 encode for proteins containing 677 and 162 amino acids, respectively. The remaining variants are not translated into a protein product.
Mutations
Somatic
A survey in the COSMIC mutation database (accession date: 17 November 2016) revealed a total of 71 mutations that lead to different modification in different human tumors. Most of the modifications are missense mutations whose functional consequences need to be addressed (Table 1).
Table 1: Cancer-associated mutations in WDR48. The table shows a detailed list of WDR48 cancer-associated mutations reported to date (November 2016) in the COSMIC mutation database, including the DNA modification (CDS Mutation), protein modification (AA mutation) and affected tissue. Missense amino acid substitutions are indicated in black, nonsense amino acid substitution in red and frameshift insertion/deletions in blue. Synonymous amino acid substitutions have been omitted.
Table 1: Cancer-associated mutations in WDR48. The table shows a detailed list of WDR48 cancer-associated mutations reported to date (November 2016) in the COSMIC mutation database, including the DNA modification (CDS Mutation), protein modification (AA mutation) and affected tissue. Missense amino acid substitutions are indicated in black, nonsense amino acid substitution in red and frameshift insertion/deletions in blue. Synonymous amino acid substitutions have been omitted.
| CDS Mutation | AA mutation | Tissue |
| c.8C>T | p.A3V | Skin |
| c.35 36GG>>AA | p.R12Q | Skin |
| c.43G>T | p.V15L | Urinary tract |
| c.53C>T | p.S18F | Skin |
| c.56A>G | p.Y19C | Haematopoietic and lymphoid |
| c.64C>T | p.R22* | Endometrium |
| c.83A>G | p.Y28C | Large intestine |
| c.88C>T | p.R30* | Large intestine |
| c.113C>T | p.L45F | NS |
| c.148C>T | p.R50* | Large intestine |
| c.175G>A | p.V59I | NS |
| c.189G>T | p.K63N | Upper aerodigestive tract |
| c.206C>T | p.A69V | Stomach |
| c.221A>G | p.H74R | Stomach |
| c. 277G>T | p.A93S | Autonomic ganglia |
| c.284C>T | p.S95F | Prostate |
| c.290C>T | p.T97M | Oesophagus |
| c. 304T>C | p.W102R | Breast |
| c.317A>G | p.K106R | Oesophagus |
| c.330G>T | p.M110I | Skin |
| c.374_375insT | p.A126fs*4 | Oesophagus |
| c.403G>T | p.A135S | Liver |
| c.504A>C | p.K168N | Large intestine |
| c.565G>A | p.E189K | Breast |
| c.585G>T | p.W195C | Stomach |
| c.610A>G | p.M204V | Haematopoietic and lymphoid |
| c.659G>C | p.R220T | Oesophagus |
| c.668C>T | p.T223M | Large intestine |
| c.682G>T | p.G228C | Small intestine |
| c.703C>T | p.R235C | Large intestine |
| c.745C>T | p.R249* | Large intestine |
| c.746G>T | p.R249L | Liver |
| c.770C>T | p.A257V | Prostate |
| c.784G>A | p.D262N | Cervix |
| c.859C>T | p.R287W | Skin |
| c.871T>G | p.C291G | Endometrium |
| c.916G>T | p.A306S | Endometrium |
| c.934A>G | p.I312V | Breast |
| c.1001C>T | p.A334V | Stomach |
| c.1006G>T | p.G336* | Liver |
| c.1007G>C | p.G33A | Urinary tract |
| c.1024T>A | p.C342S | Central nervous system |
| c.1036A>G | p.I346V | Upper aerodigestive tract |
| c.1102A>G | p.I368V | Haematopoietic and lymphoid |
| c.1210G>A | p.E404K | Cervix |
| c.1326G>T | p.W442C | Large intestine |
| c.1343C>A | p.A448D | Endometrium |
| c.1343C>T | p.A448V | Prostate |
| c.1345G>A | p.G449S | Pancreas |
| c.1434_1435insTG | p.V479fs*2 | Biliary tract |
| c.1141C>T | p.P481S | Skin |
| c.1451A>G | p.E484G | Pancreas |
| c.1486C>A | p.Q496K | Haematopoietic and lymphoid |
| c.1495C>T | p.R499* | Endometrium |
| c.1508_1524del17 | p.N504fs*10 | Ovary |
| c.1522C>T | p.Q508* | Skin |
| c.1543G>T | p.V515L | Urinary tract |
| c.1567C>T | p.R523C | Skin |
| c.1682A>G | p.K561R | Large intestine and Pancreas |
| c.1705C>T | p.L569F | Skin |
| c.1743A>C | p.K581N | Lung |
| c.1740delA | p.D583fs*75 | Biliary tract |
| c.1812T>G | p.I604M | Large intestine |
| c.1858G>A | p.E620K | Urinary tract |
| c.1870G>A | p.E624K | Large intestine and Urinary tract |
| c.1895C>T | p.A632V | Endometrium |
| c.1963C>T | p.R655* | Stomach |
| c.1969G>A | p.V657M | Skin |
| c.1989G>C | p.K663N | Lung |
| c.1999G>A | p.D667N | Skin |
| c.2017C>T | p.R673C | Breast |
Implicated in
Entity name
Note
In mice, knockout of WDR48 results is a phenotype that resembles the phenotype of human patients with Fanconi anemia (FA) (Park et al., 2013), a rare genetic disease characterized by congenital malformations, progressive bone marrow failure, genomic instability, hypersensitivity to DNA cross-linking agents and increased susceptibility to cancer (Kee and DAndrea 2012).
Entity name
Autosomal recessive spastic paraplegia type 60 (SPG60)
Note
Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders. The main pathological characteristic is the degeneration of the corticospinal tracts. Novarino and co-workers (Novarino et al., 2014) identified homozygosity for a WDR48 deletion mutant (c.1879_1881delAAG), resulting in a deletion of glutamic acid at position 628 (E628del), in a single individual from a consanguineous family that leads to spastic paraplegia type 60. The contribution of this variant to SPG60 has not been confirmed.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 24056413 | 2013 | Deubiquitinating enzyme Usp12 is a novel co-activator of the androgen receptor. | Burska UL et al |
| 18032488 | 2008 | Human papillomavirus E1 helicase interacts with the WD repeat protein p80 to promote maintenance of the viral genome in keratinocytes. | Côté-Martin A et al |
| 19075014 | 2009 | UAF1 is a subunit of multiple deubiquitinating enzyme complexes. | Cohn MA et al |
| 18082604 | 2007 | A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. | Cohn MA et al |
| 27463890 | 2016 | The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair. | Cukras S et al |
| 24356955 | 2014 | The WD40-repeat proteins WDR-20 and WDR-48 bind and activate the deubiquitinating enzyme USP-46 to promote the abundance of the glutamate receptor GLR-1 in the ventral nerve cord of Caenorhabditis elegans. | Dahlberg CL et al |
| 22195557 | 2011 | The differential modulation of USP activity by internal regulatory domains, interactors and eight ubiquitin chain types. | Faesen AC et al |
| 25833051 | 2015 | Artificial Recruitment of UAF1-USP Complexes by a PHLPP1-E1 Chimeric Helicase Enhances Human Papillomavirus DNA Replication. | Gagnon D et al |
| 24145035 | 2013 | WD repeat protein WDR48 in complex with deubiquitinase USP12 suppresses Akt-dependent cell survival signaling by stabilizing PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1). | Gangula NR et al |
| 22701671 | 2012 | Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex. | Garcia-Santisteban I et al |
| 16531995 | 2006 | Regulation of monoubiquitinated PCNA by DUB autocleavage. | Huang TT et al |
| 26077708 | 2015 | The deubiquitinating enzyme USP46 regulates AMPA receptor ubiquitination and trafficking. | Huo Y et al |
| 26811477 | 2016 | Usp12 stabilizes the T-cell receptor complex at the cell surface during signaling. | Jahan AS et al |
| 21183687 | 2011 | Regulation of histone H2A and H2B deubiquitination and Xenopus development by USP12 and USP46. | Joo HY et al |
| 23114602 | 2012 | Molecular pathogenesis and clinical management of Fanconi anemia. | Kee Y et al |
| 24850727 | 2014 | E1-mediated recruitment of a UAF1-USP deubiquitinase complex facilitates human papillomavirus DNA replication. | Lehoux M et al |
| 27373336 | 2016 | Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20. | Li H et al |
| 22391563 | 2013 | The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer. | Li X et al |
| 27239033 | 2016 | Promotion of RAD51-Mediated Homologous DNA Pairing by the RAD51AP1-UAF1 Complex. | Liang F et al |
| 25216524 | 2014 | Deubiquitinating enzyme Usp12 regulates the interaction between the androgen receptor and the Akt pathway. | McClurg UL et al |
| 21482670 | 2011 | The USP1/UAF1 complex promotes double-strand break repair through homologous recombination. | Murai J et al |
| 10819331 | 2000 | Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. | Nagase T et al |
| 15694335 | 2005 | The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. | Nijman SM et al |
| 24482476 | 2014 | Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. | Novarino G et al |
| 25855980 | 2015 | The EBNA3 family of Epstein-Barr virus nuclear proteins associates with the USP46/USP12 deubiquitination complexes to regulate lymphoblastoid cell line growth. | Ohashi M et al |
| 25744535 | 2015 | Structure-function analysis of USP1: insights into the role of Ser313 phosphorylation site and the effect of cancer-associated mutations on autocleavage. | Olazabal-Herrero A et al |
| 24001775 | 2013 | Inactivation of Uaf1 causes defective homologous recombination and early embryonic lethality in mice. | Park E et al |
| 12196293 | 2002 | Herpesviral protein targets a cellular WD repeat endosomal protein to downregulate T lymphocyte receptor expression. | Park J et al |
| 22439892 | 2012 | A noncanonical cysteine protease USP1 is activated through active site modulation by USP1-associated factor 1. | Villamil MA et al |
| 21925315 | 2011 | USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. | Williams SA et al |
| 21896657 | 2011 | Regulation of the Fanconi anemia pathway by a SUMO-like delivery network. | Yang K et al |
| 26388029 | 2015 | Structural Insights into WD-Repeat 48 Activation of Ubiquitin-Specific Protease 46. | Yin J et al |
| 27986371 | 2017 | Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway. | van Twest S et al |
Other Information
Locus ID:
NCBI: 57599
MIM: 612167
HGNC: 30914
Ensembl: ENSG00000114742
Variants:
dbSNP: 57599
ClinVar: 57599
TCGA: ENSG00000114742
COSMIC: WDR48
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38054892 | 2024 | The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses. | 0 |
| 38054892 | 2024 | The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses. | 0 |
| 33461373 | 2021 | USP1-WDR48 deubiquitinase complex enhances TGF-β induced epithelial-mesenchymal transition of TNBC cells via stabilizing TAK1. | 7 |
| 33795880 | 2021 | Structural basis of FANCD2 deubiquitination by USP1-UAF1. | 13 |
| 33461373 | 2021 | USP1-WDR48 deubiquitinase complex enhances TGF-β induced epithelial-mesenchymal transition of TNBC cells via stabilizing TAK1. | 7 |
| 33795880 | 2021 | Structural basis of FANCD2 deubiquitination by USP1-UAF1. | 13 |
| 32350107 | 2020 | The DNA-binding activity of USP1-associated factor 1 is required for efficient RAD51-mediated homologous DNA pairing and homology-directed DNA repair. | 6 |
| 32594826 | 2020 | ATAD5 suppresses centrosome over-duplication by regulating UAF1 and ID1. | 6 |
| 32350107 | 2020 | The DNA-binding activity of USP1-associated factor 1 is required for efficient RAD51-mediated homologous DNA pairing and homology-directed DNA repair. | 6 |
| 32594826 | 2020 | ATAD5 suppresses centrosome over-duplication by regulating UAF1 and ID1. | 6 |
| 30890612 | 2019 | Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes. | 8 |
| 30890612 | 2019 | Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes. | 8 |
| 28302046 | 2017 | The Role of the Complex USP1/WDR48 in Differentiation and Proliferation Processes in Cancer Stem Cells. | 5 |
| 29138248 | 2017 | USP1-UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses. | 33 |
| 28302046 | 2017 | The Role of the Complex USP1/WDR48 in Differentiation and Proliferation Processes in Cancer Stem Cells. | 5 |
Citation
Anne Olazabal-Herrero ; Godefridus J Peters ; Elisa Giovannetti ; Jose Antonio Rodriguez
WDR48 (WD repeat domain 48)
Atlas Genet Cytogenet Oncol Haematol. 2017-04-01
Online version: http://atlasgeneticsoncology.org/gene/53058/wdr48-(wd-repeat-domain-48)
