| Structural highlights
Disease
[CDC73_HUMAN] Familial isolated hyperparathyroidism;Parathyroid carcinoma;Hyperparathyroidism-jaw tumor syndrome;Familial parathyroid adenoma. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The gene represented in this entry is involved in disease pathogenesis.
Function
[CDC73_HUMAN] Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways. May be involved in cell cycle progression through the regulation of cyclin D1/PRAD1 expression. Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both indepentently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Connects PAF1C with the cleavage and polyadenylation specificity factor (CPSF) complex and the cleavage stimulation factor (CSTF) complex, and with Wnt signaling. Involved in polyadenylation of mRNA precursors.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
CDC73/Parafibromin is a critical component of the Paf1 complex (PAF1C), which is involved in transcriptional elongation and histone modifications. Mutations of the human CDC73/HRPT2 gene are associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant disorder. CDC73/parafibromin was initially recognized as a tumor suppressor by inhibiting cell proliferation via repression of cyclin D1 and c-myc genes. In recent years, it has also shown oncogenic features by activating the canonical Wnt/beta-catenin signal pathway. Here, through limited proteolysis analysis, we demonstrate that the evolutionarily conserved human CDC73 N-terminal 111 residues form a globularly folded domain (hCDC73-NTD). We have determined a crystal structure of hCDC73-NTD at 1.02 A resolution, which reveals a novel protein fold. CDC73-NTD contains an extended hydrophobic groove on its surface that may be important for its function. Most pathogenic CDC73 missense mutations associated with the HPT-JT syndrome are located in the region encoding CDC73-NTD. Our crystal and biochemical data indicate that most CDC73 missense mutations disrupt the folding of the hydrophobic core of hCDC73-NTD, while others such as the K34Q mutant reduce its thermostability. Overall, our results provide a solid structural basis for understanding the structure and function of CDC73 and its association with the HPT-JT syndrome and other diseases.
Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome.,Sun W, Kuang XL, Liu YP, Tian LF, Yan XX, Xu W Sci Rep. 2017 Nov 15;7(1):15638. doi: 10.1038/s41598-017-15715-9. PMID:29142233[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Woodard GE, Lin L, Zhang JH, Agarwal SK, Marx SJ, Simonds WF. Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene. 2005 Feb 10;24(7):1272-6. PMID:15580289 doi:http://dx.doi.org/1208274
- ↑ Rozenblatt-Rosen O, Hughes CM, Nannepaga SJ, Shanmugam KS, Copeland TD, Guszczynski T, Resau JH, Meyerson M. The parafibromin tumor suppressor protein is part of a human Paf1 complex. Mol Cell Biol. 2005 Jan;25(2):612-20. PMID:15632063 doi:http://dx.doi.org/25/2/612
- ↑ Yart A, Gstaiger M, Wirbelauer C, Pecnik M, Anastasiou D, Hess D, Krek W. The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II. Mol Cell Biol. 2005 Jun;25(12):5052-60. PMID:15923622 doi:http://dx.doi.org/25/12/5052
- ↑ Mosimann C, Hausmann G, Basler K. Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo. Cell. 2006 Apr 21;125(2):327-41. doi: 10.1016/j.cell.2006.01.053. PMID:16630820 doi:http://dx.doi.org/10.1016/j.cell.2006.01.053
- ↑ 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. Parafibromin inhibits cancer cell growth and causes G1 phase arrest. Biochem Biophys Res Commun. 2006 Nov 10;350(1):17-24. doi:, 10.1016/j.bbrc.2006.08.169. Epub 2006 Sep 7. PMID:16989776 doi:http://dx.doi.org/10.1016/j.bbrc.2006.08.169
- ↑ Rozenblatt-Rosen O, Nagaike T, Francis JM, Kaneko S, Glatt KA, Hughes CM, LaFramboise T, Manley JL, Meyerson M. The tumor suppressor Cdc73 functionally associates with CPSF and CstF 3' mRNA processing factors. Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):755-60. doi:, 10.1073/pnas.0812023106. Epub 2009 Jan 9. PMID:19136632 doi:http://dx.doi.org/10.1073/pnas.0812023106
- ↑ Chen Y, Yamaguchi Y, Tsugeno Y, Yamamoto J, Yamada T, Nakamura M, Hisatake K, Handa H. DSIF, the Paf1 complex, and Tat-SF1 have nonredundant, cooperative roles in RNA polymerase II elongation. Genes Dev. 2009 Dec 1;23(23):2765-77. doi: 10.1101/gad.1834709. PMID:19952111 doi:10.1101/gad.1834709
- ↑ Kim J, Guermah M, Roeder RG. The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS. Cell. 2010 Feb 19;140(4):491-503. doi: 10.1016/j.cell.2009.12.050. PMID:20178742 doi:10.1016/j.cell.2009.12.050
- ↑ Muntean AG, Tan J, Sitwala K, Huang Y, Bronstein J, Connelly JA, Basrur V, Elenitoba-Johnson KS, Hess JL. The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. Cancer Cell. 2010 Jun 15;17(6):609-21. doi: 10.1016/j.ccr.2010.04.012. PMID:20541477 doi:10.1016/j.ccr.2010.04.012
- ↑ Nagaike T, Logan C, Hotta I, Rozenblatt-Rosen O, Meyerson M, Manley JL. Transcriptional activators enhance polyadenylation of mRNA precursors. Mol Cell. 2011 Feb 18;41(4):409-18. doi: 10.1016/j.molcel.2011.01.022. PMID:21329879 doi:10.1016/j.molcel.2011.01.022
- ↑ Sun W, Kuang XL, Liu YP, Tian LF, Yan XX, Xu W. Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Sci Rep. 2017 Nov 15;7(1):15638. doi: 10.1038/s41598-017-15715-9. PMID:29142233 doi:http://dx.doi.org/10.1038/s41598-017-15715-9
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