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CDC73 (cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae))

Written2008-02Leslie Farber, Bin Tean Teh
Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesC1orf28
HRPT2
HRPT1
chromosome 1 open reading frame 28
hyperparathyroidism 2 (with jaw tumor)
cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae)
hyperparathyroidism 1
Alias_symbol (synonym)parafibromin
FIHP
Other aliasFLJ23316
HPT-JT
HGNC (Hugo) CDC73
LocusID (NCBI) 79577
Atlas_Id 181
Location 1q31.2  [Link to chromosome band 1q31]
Location_base_pair Starts at 193121958 and ends at 193254812 bp from pter ( according to hg19-Feb_2009)  [Mapping CDC73.png]
Fusion genes
(updated 2016)		CDC73 (1q31.2) / ABL1 (9q34.12)CDC73 (1q31.2) / FAM172A (5q15)DEGS1 (1q42.11) / CDC73 (1q31.2)
FAM172A (5q15) / CDC73 (1q31.2)HNRNPH3 (10q21.3) / CDC73 (1q31.2)
Note Defects in CDC73 are the cause of hyperparathyroidism-jaw tumor syndrome. Mutations in CDC73 are also a cause of parathyroid carcinoma (see below).

DNA/RNA

Description 17 exons (all coding)
Transcription CDC73 encodes a 2.7 kb mRNA with a 1596 bp ORF. The transcript has been detected in all tissues tested to date.

Protein

Description 531-amino acid protein (64 kD); termed parafibromin.
Expression Ubiquitously expressed
Localisation Nuclear, bipartite nuclear localization signal
Function CDC73 is a tumor suppressor gene encoding a protein called parafibromin. Parafibromin is a member of the human RNA polymerase II-associated complex, Paf1. The human Paf1 complex is composed of parafibromin, LEO1, PAF1, and CTR9. Parafibromin's interaction with this complex is dependent on its C-terminal domain, which is deleted in ca. 80% of clinically relevant mutations.
Homology Parafibromin shares 54% identity and 67% similarity with the D. melanogaster ortholog and 25% identity and 45% similarity with the C. elegans ortholog. There were no homologies to known protein domains, but moderate identity (32%) and similarity (54%) to the S. cerevisiae ortholog, Cdc73.

Mutations

Germinal Various types of mutations often leading to inactivation of protein
Somatic Various somatic inactivating mutations found in sporadic parathyroid carcinoma

Implicated in

Note
  
Entity Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT)
Disease HPT-JT is an autosomal dominant, multiple neoplasia syndrome.
Oncogenesis HPT-JT syndrome is primarily characterized by hyperparathyroidism due to parathyroid tumors. Thirty percent of individuals with HPT-JT also develop ossifying fibromas, primarily of the mandible and maxilla, which are distinct from the brown tumors associated with severe hyperparathyroidism. Kidney lesions also occur in HPT-JT as bilateral cysts, renal hamartomas or Wilms tumors.
  
  
Entity Familial isolated hyperthyroidism
Disease Familial isolated primary hyperparathyroidism is an autosomal dominant disorder that can represent an early stage of either the multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor (HPT-JT) syndromes; or alternatively caused by a distinct entity involving another locus.
  
  
Entity Sporadic parathyroid carcinoma
Disease These cancers characteristically result in more profound clinical manifestations of hyperparathyroidism than do parathyroid adenomas. Parathyroid carcinomas cause hyperparathyroidism. The hyperparathyroidism is usually severe, with high serum calcium level, severe bone disease, and renal stones.
Prognosis 5-years survival rate is between 50% and 70%.
Oncogenesis Loss of parafibromin expression strongly predicts parathyroid malignancy
  
  
Entity Sporadic Renal Tumors
Cytogenetics Loss of heterozygosity (LOH) of HRPT2 was found in clear cell , papillary, chromophobe renal cell carcinomas, oncocytomas, and Wilms tumors. In addition, two novel HRPT2 point mutations were detected in clear cell carcinoma and Wilms tumor.
  

Bibliography

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.
Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Höög A, Heath H 3rd, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo LO, Besser GM, Jackson CE, Morreau H, Trent JM, Thakker RV, Marx SJ, Teh BT, Larsson C, Hobbs MR
Nature genetics. 2002 ; 32 (4) : 676-680.
PMID 12434154
 
Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene.
Cavaco BM, Guerra L, Bradley KJ, Carvalho D, Harding B, Oliveira A, Santos MA, Sobrinho LG, Thakker RV, Leite V
The Journal of clinical endocrinology and metabolism. 2004 ; 89 (4) : 1747-1752.
PMID 15070940
 
Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation.
Cetani F, Pardi E, Ambrogini E, Viacava P, Borsari S, Lemmi M, Cianferotti L, Miccoli P, Pinchera A, Arnold A, Marcocci C
Endocrine-related cancer. 2007 ; 14 (2) : 493-499.
PMID 17639062
 
Nucleolar localization of parafibromin is mediated by three nucleolar localization signals.
Hahn MA, Marsh DJ
FEBS letters. 2007 ; 581 (26) : 5070-5074.
PMID 17923126
 
Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype.
Haven CJ, Howell VM, Eilers PH, Dunne R, Takahashi M, van Puijenbroek M, Furge K, Kievit J, Tan MH, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Dralle H, Hoang-Vu C, Gimm O, Morreau H, Marsh DJ, Teh BT
Cancer research. 2004 ; 64 (20) : 7405-7411.
PMID 15492263
 
HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours.
Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Marsh DJ, Morreau H, Teh BT
Journal of medical genetics. 2003 ; 40 (9) : 657-663.
PMID 12960210
 
Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification.
Juhlin CC, Villablanca A, Sandelin K, Haglund F, Nordenström J, Forsberg L, Bränström R, Obara T, Arnold A, Larsson C, Höög A
Endocrine-related cancer. 2007 ; 14 (2) : 501-512.
PMID 17639063
 
Nuclear localization of the parafibromin tumor suppressor protein implicated in the hyperparathyroidism-jaw tumor syndrome enhances its proapoptotic function.
Lin L, Czapiga M, Nini L, Zhang JH, Simonds WF
Molecular cancer research : MCR. 2007 ; 5 (2) : 183-193.
PMID 17314275
 
Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.
Liontos M, Koutsami M, Sideridou M, Evangelou K, Kletsas D, Levy B, Kotsinas A, Nahum O, Zoumpourlis V, Kouloukoussa M, Lygerou Z, Taraviras S, Kittas C, Bartkova J, Papavassiliou AG, Bartek J, Halazonetis TD, Gorgoulis VG
Cancer research. 2007 ; 67 (22) : 10899-10909.
PMID 18006835
 
Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome.
Mizusawa N, Uchino S, Iwata T, Tsuyuguchi M, Suzuki Y, Mizukoshi T, Yamashita Y, Sakurai A, Suzuki S, Beniko M, Tahara H, Fujisawa M, Kamata N, Fujisawa K, Yashiro T, Nagao D, Golam HM, Sano T, Noguchi S, Yoshimoto K
Clinical endocrinology. 2006 ; 65 (1) : 9-16.
PMID 16817812
 
Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo.
Mosimann C, Hausmann G, Basler K
Cell. 2006 ; 125 (2) : 327-341.
PMID 16630820
 
The parafibromin tumor suppressor protein is part of a human Paf1 complex.
Rozenblatt-Rosen O, Hughes CM, Nannepaga SJ, Shanmugam KS, Copeland TD, Guszczynski T, Resau JH, Meyerson M
Molecular and cellular biology. 2005 ; 25 (2) : 612-620.
PMID 15632063
 
Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma.
Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD, Farnebo LO, Larsson C, Arnold A
The New England journal of medicine. 2003 ; 349 (18) : 1722-1729.
PMID 14585940
 
Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome.
Simonds WF, Robbins CM, Agarwal SK, Hendy GN, Carpten JD, Marx SJ
The Journal of clinical endocrinology and metabolism. 2004 ; 89 (1) : 96-102.
PMID 14715834
 
HRPT2, a tumor suppressor gene for hyperparathyroidism-jaw tumor syndrome.
Wang PF, Tan MH, Zhang C, Morreau H, Teh BT
Hormone and metabolic research. Hormon- und Stoffwechselforschung. Hormones et metabolisme. 2005 ; 37 (6) : 380-383.
PMID 16001331
 
Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression.
Woodard GE, Lin L, Zhang JH, Agarwal SK, Marx SJ, Simonds WF
Oncogene. 2005 ; 24 (7) : 1272-1276.
PMID 15580289
 
The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.
Yart A, Gstaiger M, Wirbelauer C, Pecnik M, Anastasiou D, Hess D, Krek W
Molecular and cellular biology. 2005 ; 25 (12) : 5052-5060.
PMID 15923622
 
Parafibromin inhibits cancer cell growth and causes G1 phase arrest.
Zhang C, Kong D, Tan MH, Pappas DL Jr, Wang PF, Chen J, Farber L, Zhang N, Koo HM, Weinreich M, Williams BO, Teh BT
Biochemical and biophysical research communications. 2006 ; 350 (1) : 17-24.
PMID 16989776
 
Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene.
Zhao J, Yart A, Frigerio S, Perren A, Schraml P, Weisstanner C, Stallmach T, Krek W, Moch H
Oncogene. 2007 ; 26 (23) : 3440-3449.
PMID 17130827
 

Citation

This paper should be referenced as such :
Farber, L ; Teh, BT. CDC73 (cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S
cerevisiae))
Atlas Genet Cytogenet Oncol Haematol. 2008;12(6):425-427.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CDC73ID181ch1q31.html

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Hyperparathyroidism-Jaw tumor syndrome (HPT-JT)

External links

Nomenclature
HGNC (Hugo)CDC73   16783
LRG (Locus Reference Genomic)LRG_507
Cards
AtlasCDC73ID181ch1q31
Entrez_Gene (NCBI)CDC73  79577  cell division cycle 73
AliasesC1orf28; FIHP; HPTJT; HRPT1; 
HRPT2; HYX
GeneCards (Weizmann)CDC73
Ensembl hg19 (Hinxton)ENSG00000134371 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000134371 [Gene_View]  chr1:193121958-193254812 [Contig_View]  CDC73 [Vega]
ICGC DataPortalENSG00000134371
TCGA cBioPortalCDC73
AceView (NCBI)CDC73
Genatlas (Paris)CDC73
WikiGenes79577
SOURCE (Princeton)CDC73
Genetics Home Reference (NIH)CDC73
Genomic and cartography
GoldenPath hg38 (UCSC)CDC73  -     chr1:193121958-193254812 +  1q31.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CDC73  -     1q31.2   [Description]    (hg19-Feb_2009)
EnsemblCDC73 - 1q31.2 [CytoView hg19]  CDC73 - 1q31.2 [CytoView hg38]
Mapping of homologs : NCBICDC73 [Mapview hg19]  CDC73 [Mapview hg38]
OMIM607393   608266   
Gene and transcription
Genbank (Entrez)AF312865 AI638120 AK026969 AK226038 AK300929
RefSeq transcript (Entrez)NM_024529
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CDC73
Cluster EST : UnigeneHs.378996 [ NCBI ]
CGAP (NCI)Hs.378996
Alternative Splicing GalleryENSG00000134371
Gene ExpressionCDC73 [ NCBI-GEO ]   CDC73 [ EBI - ARRAY_EXPRESS ]   CDC73 [ SEEK ]   CDC73 [ MEM ]
Gene Expression Viewer (FireBrowse)CDC73 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)79577
GTEX Portal (Tissue expression)CDC73
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6P1J9   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6P1J9  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6P1J9
Splice isoforms : SwissVarQ6P1J9
PhosPhoSitePlusQ6P1J9
Domains : Interpro (EBI)Cdc73/Parafibromin    CDC73_C    Cdc73_N   
Domain families : Pfam (Sanger)CDC73_C (PF05179)    CDC73_N (PF16050)   
Domain families : Pfam (NCBI)pfam05179    pfam16050   
Conserved Domain (NCBI)CDC73
DMDM Disease mutations79577
Blocks (Seattle)CDC73
SuperfamilyQ6P1J9
Human Protein AtlasENSG00000134371
Peptide AtlasQ6P1J9
HPRD09581
IPIIPI00300659   IPI00909174   
Protein Interaction databases
DIP (DOE-UCLA)Q6P1J9
IntAct (EBI)Q6P1J9
FunCoupENSG00000134371
BioGRIDCDC73
STRING (EMBL)CDC73
ZODIACCDC73
Ontologies - Pathways
QuickGOQ6P1J9
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  nuclear chromosome, telomeric region  RNA polymerase II core binding  transcription factor activity, RNA polymerase II transcription factor binding  regulation of cell growth  endodermal cell fate commitment  protein binding  nucleus  nucleoplasm  cytosol  transcription from RNA polymerase II promoter  transcription elongation from RNA polymerase II promoter  mRNA polyadenylation  cell cycle  negative regulation of cell proliferation  histone monoubiquitination  Wnt signaling pathway  protein ubiquitination  Cdc73/Paf1 complex  stem cell population maintenance  positive regulation of Wnt signaling pathway  positive regulation of mRNA 3'-end processing  protein destabilization  positive regulation of transcription elongation from RNA polymerase II promoter  histone H2B ubiquitination  recruitment of 3'-end processing factors to RNA polymerase II holoenzyme complex  negative regulation of apoptotic process  negative regulation of myeloid cell differentiation  positive regulation of transcription from RNA polymerase II promoter  negative regulation of fibroblast proliferation  negative regulation of epithelial cell proliferation  cellular response to lipopolysaccharide  beta-catenin-TCF complex assembly  negative regulation of G1/S transition of mitotic cell cycle  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  nuclear chromosome, telomeric region  RNA polymerase II core binding  transcription factor activity, RNA polymerase II transcription factor binding  regulation of cell growth  endodermal cell fate commitment  protein binding  nucleus  nucleoplasm  cytosol  transcription from RNA polymerase II promoter  transcription elongation from RNA polymerase II promoter  mRNA polyadenylation  cell cycle  negative regulation of cell proliferation  histone monoubiquitination  Wnt signaling pathway  protein ubiquitination  Cdc73/Paf1 complex  stem cell population maintenance  positive regulation of Wnt signaling pathway  positive regulation of mRNA 3'-end processing  protein destabilization  positive regulation of transcription elongation from RNA polymerase II promoter  histone H2B ubiquitination  recruitment of 3'-end processing factors to RNA polymerase II holoenzyme complex  negative regulation of apoptotic process  negative regulation of myeloid cell differentiation  positive regulation of transcription from RNA polymerase II promoter  negative regulation of fibroblast proliferation  negative regulation of epithelial cell proliferation  cellular response to lipopolysaccharide  beta-catenin-TCF complex assembly  negative regulation of G1/S transition of mitotic cell cycle  
REACTOMEQ6P1J9 [protein]
REACTOME PathwaysR-HSA-8866654 [pathway]   
NDEx NetworkCDC73
Atlas of Cancer Signalling NetworkCDC73
Wikipedia pathwaysCDC73
Orthology - Evolution
OrthoDB79577
GeneTree (enSembl)ENSG00000134371
Phylogenetic Trees/Animal Genes : TreeFamCDC73
HOVERGENQ6P1J9
HOGENOMQ6P1J9
Homologs : HomoloGeneCDC73
Homology/Alignments : Family Browser (UCSC)CDC73
Gene fusions - Rearrangements
Fusion : MitelmanCDC73/FAM172A [1q31.2/5q15]  
Fusion : MitelmanFAM172A/CDC73 [5q15/1q31.2]  [t(1;5)(q31;q15)]  
Fusion: TCGACDC73 1q31.2 FAM172A 5q15 LAML
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCDC73 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CDC73
dbVarCDC73
ClinVarCDC73
1000_GenomesCDC73 
Exome Variant ServerCDC73
ExAC (Exome Aggregation Consortium)CDC73 (select the gene name)
Genetic variants : HAPMAP79577
Genomic Variants (DGV)CDC73 [DGVbeta]
DECIPHERCDC73 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCDC73 
Mutations
ICGC Data PortalCDC73 
TCGA Data PortalCDC73 
Broad Tumor PortalCDC73
OASIS PortalCDC73 [ Somatic mutations - Copy number]
Cancer Gene: CensusCDC73 
Somatic Mutations in Cancer : COSMICCDC73  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCDC73
intOGen PortalCDC73
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Zhejiang University Center for Genetic and Genomic Medicine (ZJU-CGGM)
BioMutasearch CDC73
DgiDB (Drug Gene Interaction Database)CDC73
DoCM (Curated mutations)CDC73 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CDC73 (select a term)
intoGenCDC73
NCG5 (London)CDC73
Cancer3DCDC73(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607393    608266   
Orphanet8675    8675    14452    14453   
MedgenCDC73
Genetic Testing Registry CDC73
NextProtQ6P1J9 [Medical]
TSGene79577
GENETestsCDC73
Target ValidationCDC73
Huge Navigator CDC73 [HugePedia]
snp3D : Map Gene to Disease79577
BioCentury BCIQCDC73
ClinGenCDC73
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD79577
Chemical/Pharm GKB GenePA29464
Clinical trialCDC73
Miscellaneous
canSAR (ICR)CDC73 (select the gene name)
Probes
Litterature
PubMed134 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCDC73
EVEXCDC73
GoPubMedCDC73
iHOPCDC73
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Jun 30 11:03:04 CEST 2017
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