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

2008-02-01 Leslie Farber , Bin Tean Teh Affiliation

Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA

Identity

HGNC

CDC73

LOCATION

1q31.2

LOCUSID

79577

ALIAS

C1orf28,FIHP,HPTJT,HRPT1,HRPT2,HYX

FUSION GENES

Show Gene Fusions

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.

Proteins

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. Parafibromins 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

Entity name

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 name

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 name

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 name

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.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
12434154	2002	HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.	Carpten JD et al
15070940	2004	Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene.	Cavaco BM et al
17639062	2007	Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation.	Cetani F et al
17923126	2007	Nucleolar localization of parafibromin is mediated by three nucleolar localization signals.	Hahn MA et al
15492263	2004	Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype.	Haven CJ et al
12960210	2003	HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours.	Howell VM et al
17639063	2007	Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification.	Juhlin CC et al
17314275	2007	Nuclear localization of the parafibromin tumor suppressor protein implicated in the hyperparathyroidism-jaw tumor syndrome enhances its proapoptotic function.	Lin L et al
18006835	2007	Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.	Liontos M et al
16817812	2006	Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome.	Mizusawa N et al
16630820	2006	Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo.	Mosimann C et al
15632063	2005	The parafibromin tumor suppressor protein is part of a human Paf1 complex.	Rozenblatt-Rosen O et al
14585940	2003	Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma.	Shattuck TM et al
14715834	2004	Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome.	Simonds WF et al
16001331	2005	HRPT2, a tumor suppressor gene for hyperparathyroidism-jaw tumor syndrome.	Wang PF et al
15580289	2005	Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression.	Woodard GE et al
15923622	2005	The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.	Yart A et al
16989776	2006	Parafibromin inhibits cancer cell growth and causes G1 phase arrest.	Zhang C et al
17130827	2007	Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene.	Zhao J et al

Other Information

Locus ID:

NCBI: 79577
MIM: 607393
HGNC: 16783
Ensembl: ENSG00000134371

Variants:

dbSNP: 79577
ClinVar: 79577
TCGA: ENSG00000134371
COSMIC: CDC73

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000134371	ENST00000367435	Q6P1J9
ENSG00000134371	ENST00000635846	A0A1B0GUB2
ENSG00000134371	ENST00000643006	A0A2R8YHB3
ENSG00000134371	ENST00000643784	A0A2R8Y640
ENSG00000134371	ENST00000648071	A0A3B3ISN2
ENSG00000134371	ENST00000650197	A0A3B3IRP5

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Signal Transduction	REACTOME	R-HSA-162582
Signaling by Wnt	REACTOME	R-HSA-195721
TCF dependent signaling in response to WNT	REACTOME	R-HSA-201681
Formation of the beta-catenin:TCF transactivating complex	REACTOME	R-HSA-201722
Signaling by Hedgehog	REACTOME	R-HSA-5358351
Hedgehog 'on' state	REACTOME	R-HSA-5632684
Gene Expression	REACTOME	R-HSA-74160
RNA Polymerase II Transcription	REACTOME	R-HSA-73857
RNA Polymerase II Pre-transcription Events	REACTOME	R-HSA-674695
RNA Polymerase II Transcription Elongation	REACTOME	R-HSA-75955
Formation of RNA Pol II elongation complex	REACTOME	R-HSA-112382
Protein ubiquitination	REACTOME	R-HSA-8852135
E3 ubiquitin ligases ubiquitinate target proteins	REACTOME	R-HSA-8866654

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37855385	2024	Targeting UBR5 inhibits postsurgical breast cancer lung metastases by inducing CDC73 and p53 mediated apoptosis.	2
37855385	2024	Targeting UBR5 inhibits postsurgical breast cancer lung metastases by inducing CDC73 and p53 mediated apoptosis.	2
36255176	2023	The clinicopathological and prognostic significances of CDC73 expression in breast cancer: A pathological and bioinformatics analysis.	2
36739170	2023	Para This, Fibromin That: The Role of CDC73 in Parathyroid Tumors and Familial Tumor Syndromes.	1
36255176	2023	The clinicopathological and prognostic significances of CDC73 expression in breast cancer: A pathological and bioinformatics analysis.	2
36739170	2023	Para This, Fibromin That: The Role of CDC73 in Parathyroid Tumors and Familial Tumor Syndromes.	1
34729685	2022	A novel long-range deletion spanning CDC73 and upper-stream genes discovered in a kindred of familial primary hyperparathyroidism.	2
36177768	2022	Heterozygous CDC73 mutation causing hyperparathyroidism in children and adolescents: a report of 2 cases.	1
34729685	2022	A novel long-range deletion spanning CDC73 and upper-stream genes discovered in a kindred of familial primary hyperparathyroidism.	2
36177768	2022	Heterozygous CDC73 mutation causing hyperparathyroidism in children and adolescents: a report of 2 cases.	1
34424918	2021	Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex.	1
34424918	2021	Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex.	1
31595586	2020	Tumor predisposition in an individual with chromosomal rearrangements of 1q31.2-q41 encompassing cell division cycle protein 73.	1
32780442	2020	The Oncosuppressors MEN1 and CDC73 Are Involved in lncRNA Deregulation in Human Parathyroid Tumors.	6
31595586	2020	Tumor predisposition in an individual with chromosomal rearrangements of 1q31.2-q41 encompassing cell division cycle protein 73.	1

Citation

Leslie Farber ; Bin Tean Teh

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

Atlas Genet Cytogenet Oncol Haematol. 2008-02-01

Online version: http://atlasgeneticsoncology.org/gene/181