WDR48 (WD repeat domain 48)

2017-04-01   Anne Olazabal-Herrero , Godefridus J Peters , Elisa Giovannetti , Jose Antonio Rodriguez 

Identity

HGNC
LOCATION
3p22.2 (Starts at 39051986 and ends at 39096671 bp from pter (according to hg-38))
IMAGE
Atlas 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.

Pseudogene

Not reported pseudogenes. Paralogs for WDR48 are STRN4 and STRN3.

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.
CDS MutationAA mutationTissue
c.8C>Tp.A3VSkin
c.35 36GG>>AAp.R12QSkin
c.43G>Tp.V15LUrinary tract
c.53C>Tp.S18FSkin
c.56A>Gp.Y19CHaematopoietic and lymphoid
c.64C>Tp.R22*Endometrium
c.83A>Gp.Y28CLarge intestine
c.88C>Tp.R30*Large intestine
c.113C>Tp.L45FNS
c.148C>Tp.R50*Large intestine
c.175G>Ap.V59INS
c.189G>Tp.K63NUpper aerodigestive tract
c.206C>Tp.A69VStomach
c.221A>Gp.H74RStomach
c. 277G>Tp.A93SAutonomic ganglia
c.284C>Tp.S95FProstate
c.290C>Tp.T97MOesophagus
c. 304T>Cp.W102RBreast
c.317A>Gp.K106ROesophagus
c.330G>Tp.M110ISkin
c.374_375insTp.A126fs*4Oesophagus
c.403G>Tp.A135SLiver
c.504A>Cp.K168NLarge intestine
c.565G>Ap.E189KBreast
c.585G>Tp.W195CStomach
c.610A>Gp.M204VHaematopoietic and lymphoid
c.659G>Cp.R220TOesophagus
c.668C>Tp.T223MLarge intestine
c.682G>Tp.G228CSmall intestine
c.703C>Tp.R235CLarge intestine
c.745C>Tp.R249*Large intestine
c.746G>Tp.R249LLiver
c.770C>Tp.A257VProstate
c.784G>Ap.D262NCervix
c.859C>Tp.R287WSkin
c.871T>Gp.C291GEndometrium
c.916G>Tp.A306SEndometrium
c.934A>Gp.I312VBreast
c.1001C>Tp.A334VStomach
c.1006G>Tp.G336*Liver
c.1007G>Cp.G33AUrinary tract
c.1024T>Ap.C342SCentral nervous system
c.1036A>Gp.I346VUpper aerodigestive tract
c.1102A>Gp.I368VHaematopoietic and lymphoid
c.1210G>Ap.E404KCervix
c.1326G>Tp.W442CLarge intestine
c.1343C>Ap.A448DEndometrium
c.1343C>Tp.A448VProstate
c.1345G>Ap.G449SPancreas
c.1434_1435insTGp.V479fs*2Biliary tract
c.1141C>Tp.P481SSkin
c.1451A>Gp.E484GPancreas
c.1486C>Ap.Q496KHaematopoietic and lymphoid
c.1495C>Tp.R499*Endometrium
c.1508_1524del17p.N504fs*10Ovary
c.1522C>Tp.Q508*Skin
c.1543G>Tp.V515LUrinary tract
c.1567C>Tp.R523CSkin
c.1682A>Gp.K561RLarge intestine and Pancreas
c.1705C>Tp.L569FSkin
c.1743A>Cp.K581NLung
c.1740delAp.D583fs*75Biliary tract
c.1812T>Gp.I604MLarge intestine
c.1858G>Ap.E620KUrinary tract
c.1870G>Ap.E624KLarge intestine and Urinary tract
c.1895C>Tp.A632VEndometrium
c.1963C>Tp.R655*Stomach
c.1969G>Ap.V657MSkin
c.1989G>Cp.K663NLung
c.1999G>Ap.D667NSkin
c.2017C>Tp.R673CBreast

Implicated in

Entity name
Fanconi anaemia
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.

Bibliography

Pubmed IDLast YearTitleAuthors
240564132013Deubiquitinating enzyme Usp12 is a novel co-activator of the androgen receptor.Burska UL et al
180324882008Human papillomavirus E1 helicase interacts with the WD repeat protein p80 to promote maintenance of the viral genome in keratinocytes.Côté-Martin A et al
190750142009UAF1 is a subunit of multiple deubiquitinating enzyme complexes.Cohn MA et al
180826042007A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway.Cohn MA et al
274638902016The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair.Cukras S et al
243569552014The 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
221955572011The differential modulation of USP activity by internal regulatory domains, interactors and eight ubiquitin chain types.Faesen AC et al
258330512015Artificial Recruitment of UAF1-USP Complexes by a PHLPP1-E1 Chimeric Helicase Enhances Human Papillomavirus DNA Replication.Gagnon D et al
241450352013WD 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
227016712012Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex.Garcia-Santisteban I et al
165319952006Regulation of monoubiquitinated PCNA by DUB autocleavage.Huang TT et al
260777082015The deubiquitinating enzyme USP46 regulates AMPA receptor ubiquitination and trafficking.Huo Y et al
268114772016Usp12 stabilizes the T-cell receptor complex at the cell surface during signaling.Jahan AS et al
211836872011Regulation of histone H2A and H2B deubiquitination and Xenopus development by USP12 and USP46.Joo HY et al
231146022012Molecular pathogenesis and clinical management of Fanconi anemia.Kee Y et al
248507272014E1-mediated recruitment of a UAF1-USP deubiquitinase complex facilitates human papillomavirus DNA replication.Lehoux M et al
273733362016Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20.Li H et al
223915632013The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer.Li X et al
272390332016Promotion of RAD51-Mediated Homologous DNA Pairing by the RAD51AP1-UAF1 Complex.Liang F et al
252165242014Deubiquitinating enzyme Usp12 regulates the interaction between the androgen receptor and the Akt pathway.McClurg UL et al
214826702011The USP1/UAF1 complex promotes double-strand break repair through homologous recombination.Murai J et al
108193312000Prediction 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
156943352005The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway.Nijman SM et al
244824762014Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.Novarino G et al
258559802015The 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
257445352015Structure-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
240017752013Inactivation of Uaf1 causes defective homologous recombination and early embryonic lethality in mice.Park E et al
121962932002Herpesviral protein targets a cellular WD repeat endosomal protein to downregulate T lymphocyte receptor expression.Park J et al
224398922012A noncanonical cysteine protease USP1 is activated through active site modulation by USP1-associated factor 1.Villamil MA et al
219253152011USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma.Williams SA et al
218966572011Regulation of the Fanconi anemia pathway by a SUMO-like delivery network.Yang K et al
263880292015Structural Insights into WD-Repeat 48 Activation of Ubiquitin-Specific Protease 46.Yin J et al
279863712017Mechanism 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

Gene IDTranscript IDUniprot
ENSG00000114742ENST00000302313Q8TAF3
ENSG00000114742ENST00000302313A0A024R2L1
ENSG00000114742ENST00000413099F8W7Y5
ENSG00000114742ENST00000420940F8W9K4
ENSG00000114742ENST00000423296F8W7Q3
ENSG00000114742ENST00000433841F8W6P2
ENSG00000114742ENST00000441361C9JC24

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45

Pathways

PathwaySourceExternal ID
Fanconi anemia pathwayKEGGko03460
Fanconi anemia pathwayKEGGhsa03460
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
DeubiquitinationREACTOMER-HSA-5688426
Ub-specific processing proteasesREACTOMER-HSA-5689880

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
190750142009UAF1 is a subunit of multiple deubiquitinating enzyme complexes.81
201477372010WDR20 regulates activity of the USP12 x UAF1 deubiquitinating enzyme complex.41
180324882008Human papillomavirus E1 helicase interacts with the WD repeat protein p80 to promote maintenance of the viral genome in keratinocytes.26
241450352013WD 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).24
231161192012Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1.15
273733362016Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20.13
248507272014E1-mediated recruitment of a UAF1-USP deubiquitinase complex facilitates human papillomavirus DNA replication.11
274638902016The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair.11
222782512012Inhibition of human papillomavirus DNA replication by an E1-derived p80/UAF1-binding peptide.8
227016712012Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex.8

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