View source for UBTF

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Upstream binding transcription factor (UBTF)''', or upstream binding factor (UBF), is a [[protein]] that in humans is encoded by the ''UBTF'' [[gene]].<ref name="pmid9126496">{{cite journal | vauthors = Matera AG, Wu W, Imai H, O'Keefe CL, Chan EK | title = Molecular cloning of the RNA polymerase I transcription factor hUBF/NOR-90 (UBTF) gene and localization to 17q21.3 by fluorescence in situ hybridization and radiation hybrid mapping | journal = Genomics | volume = 41 | issue = 1 | pages = 135–8  | date = May 1997 | pmid = 9126496 | doi = 10.1006/geno.1997.4647 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: UBTF upstream binding transcription factor, RNA polymerase I| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7343}}</ref>
== Gene ==
In humans, the ''UBTF'' gene encodes a 764 amino acid protein and is located on chromosome 17 at position q21.31.<ref>{{cite journal | vauthors = Jones KA, Black DM, Griffiths BL, Solomon E | title = Localization of the Human RNA Polymerase I Transcription Factor Gene (UBTF) to the D17S183 Locus on Chromosome 17q21 and Construction of a Long-Range Restriction Map of the Region | journal = Genomics | volume = 30 | issue = 3 | pages = 602–4  | date = Dec 1995 | doi = 10.1006/geno.1995.1283 | pmid = 8825649 }}</ref><ref>{{cite journal | vauthors = Edvardson S, Nicolae CM, Agrawal PB, Mignot C, Payne K, et al. | title = Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood | journal = American Journal of Human Genetics | volume = 101 | issue = 2 | pages = 267–73 | date = Aug 2017 | doi = 10.1016/j.ajhg.2017.07.002 | pmid = 28777933 | pmc = 5544390 }}</ref> In mice, ''UBTF'' is found on chromosome 11 {{Citation needed|date=April 2023}}.
== Structure ==
UBTF contains six high mobility group boxes ([[HMG-box|HMG-boxes]]) that allow it to bind to DNA.<ref name="pmid25452314">{{cite journal | vauthors = Sanij E, Diesch J, Lesmana A, Poortinga G, Hein N, et al. | title = A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes | journal = Genome Res | volume = 25 | issue = 2 | pages = 201–12  | date = Feb 2015 | pmid = 25452314 | doi = 10.1101/gr.176115.114| pmc = 4315294 }}</ref> UBTF also contains a hyperacidic carboxy-terminal domain, which is required for transcription activation, and a helix-gap-helix dimersation motif (as UBTF is thought to often act as a dimer).<ref name="pmid25452314">{{cite journal | vauthors = Sanij E, Diesch J, Lesmana A, Poortinga G, Hein N, et al. | title = A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes | journal = Genome Res | volume = 25 | issue = 2 | pages = 201–12  | date = Feb 2015 | pmid = 25452314 | doi = 10.1101/gr.176115.114| pmc = 4315294 }}</ref><ref name="pmid394792">{{cite journal | vauthors = Schnapp G, Santori F, Carles C, Riva M, Grummt I | title = The HMG box-containing nucleolar transcription factor UBF interacts with a specific subunit of RNA polymerase I | journal = EMBO J | volume = 13 | issue = 1 | pages = 190–9  | date = Jan 1994 | pmid = 394792 | doi = 10.1002/j.1460-2075.1994.tb06248.x | pmc = 394792 }}</ref>
In humans, alternative splicing can give rise to either the UBTF1 or UBTF2 isoform which are 97 kD and 94 kD in mass, respectively <ref name="pmid3413483">{{cite journal | vauthors = Bell SP, Learned RM, Jantzen HM, Tjian R | title = Functional cooperativity between transcription factors UBF1 and SL1 mediates human ribosomal RNA synthesis | journal = Science | volume = 241 | issue = 4870 | pages = 1192–7  | date = Sep 1988 | pmid = 3413483 | doi = 10.1126/science.3413483 | bibcode = 1988Sci...241.1192B }}</ref> UBTF2 lacks exon 8 of the larger UBTF1 isoform which encodes a portion of HMG Box 2.<ref name="pmid29300972">{{cite journal | vauthors = Toro C, Hori RT, Malicdan MC, Tifft CJ, Goldstein A, et al. | title = A recurrent de novo missense mutation in UBTF causes developmental neuroregression | journal = EMBO J | volume = 27 | issue = 4 | pages = 691–705  | date = Feb 2018 | pmid = 29300972 | doi = 10.1093/hmg/ddx435 | pmc = 5886272 }}</ref>
== Function ==
UBTF is a transcription factor required for expression of the 18S, 5.8S, and 28S ribosomal RNAs, along with SL1 (a complex of TBP (MIM 600075) and three TBP-associated factors or 'TAFs'){{Citation needed|date=April 2023}}.
UBTF is a nucleolar phosphoprotein with both DNA binding and transactivation domains. Sequence-specific DNA binding to the core and upstream control elements of the human rRNA promoter is mediated through several HMG boxes.<ref name="pmid2330041">{{cite journal | vauthors = Jantzen HM, Admon A, Bell SP, Tjian R | title = Nucleolar transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins | journal = Nature | volume = 344 | issue = 6269 | pages = 830–6  | date = Apr 1990 | pmid = 2330041 | doi = 10.1038/344830a0 | bibcode = 1990Natur.344..830J | s2cid = 4280039 | doi-access = free }}</ref> [supplied by OMIM]<ref name="entrez" />
In vertebrates, UBTF plays a crucial role in maintaining rDNA chromatin in a euchromatic state. Consequently, UBTF binding is one of the characteristics of euchromatic, transcriptionally active rDNA repeats.<ref name="pmid19717978">{{cite journal | vauthors = Sanij E, Hannan R | title = The role of UBF in regulating the structure and dynamics of transcriptionally active rDNA chromatin | journal = Epigenetics | volume = 4 | issue = 6 | pages = 374–82  | date = Aug 2009 | pmid = 19717978 | doi = 10.4161/epi.4.6.9449 | s2cid = 30922645 | doi-access = free }}</ref>
UBTF2 has been found to regulate mRNA transcription by RNA Polymerase II.<ref name="pmid25452314">{{cite journal | vauthors = Sanij E, Diesch J, Lesmana A, Poortinga G, Hein N, et al. | title = A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes | journal = Genome Res | volume = 25 | issue = 2 | pages = 201–12  | date = Feb 2015 | pmid = 25452314 | doi = 10.1101/gr.176115.114| pmc = 4315294 }}</ref>
== Clinical significance ==
UBTF may have a role in cancer. Increased UBF binding to rDNA has been observed in cancer cells and is associated with elevated rDNA transcription and tumor cell survival.<ref>{{cite journal | vauthors = Diesch J, Bywater MJ, Sanij E, Cameron DP, Schierding W, et al. | title = Changes in long-range rDNA-genomic interactions associate with altered RNA polymerase II gene programs during malignant transformation | journal = Communications Biology | volume = 2 | pages = e39(2019) | date = Jan 2019 | doi = 10.1038/s42003-019-0284-y | pmid = 30701204 | s2cid = 210151479 | pmc = 6349880 }}</ref> Supporting this, it was found that cisplatin, a chemotherapy drug, can displace UBTF from rDNA, causing a reduction in rRNA synthesis and subsequent p53-independent apoptosis.<ref name="pmid26317157">{{cite journal | vauthors = Hamdane N, Herdman C, Mars J, Stefanovsky V, Tremblay MG, Moss T | title = Depletion of the cisplatin targeted HMGB-box factor UBF selectively induces p53-independent apoptotic death in transformed cells | journal = Oncotarget | volume = 6 | issue = 29 | pages = 27519–27536  | date = Sep 2015 | pmid = 26317157 | doi = 10.18632/oncotarget.4823 | pmc = 4695006 }}</ref>
Additionally, UBTF has been found to facilitate melanoma by promoting GIT1 expression which, in turn, activates MEK1/2-ERK1/2 signaling pathways.<ref>{{cite journal | vauthors = Zhang J, Zhang J, Liu W, Ge R, Gao T, et al. | title = UBTF facilitates melanoma progression via modulating MEK1/2-ERK1/2 signalling pathways by promoting GIT1 transcription | journal = Cancer Cell International | volume = 21 | pages = 543(2021) | date = Oct 2021 | issue = 1 | doi = 10.1186/s12935-021-02237-8 | pmid = 34663332 | pmc = 8522148 | doi-access = free }}</ref>
UBTF may also be important to neurological functioning. A ''de novo'' gain-of-function mutation to UBTF (c.628G>A) has been found to cause developmental neuroregression.<ref name="pmid29300972">{{cite journal | vauthors = Toro C, Hori RT, Malicdan MC, Tifft CJ, Goldstein A, et al. | title = A recurrent de novo missense mutation in UBTF causes developmental neuroregression | journal = EMBO J | volume = 27 | issue = 4 | pages = 691–705  | date = Feb 2018 | pmid = 29300972 | doi = 10.1093/hmg/ddx435 | pmc = 5886272 }}</ref> This mutation replaces glutamic acid with lysine at position 210 of the polypeptide chain (p.Glu210Lys) which results in a stronger UBTF interaction with DNA.<ref>{{cite journal | vauthors = Edvardson S, Nicolae CM, Agrawal PB, Mignot C, Payne K, et al. | title = Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood | journal = American Journal of Human Genetics | volume = 101 | issue = 2 | pages = 267–73 | date = Aug 2017 | doi = 10.1016/j.ajhg.2017.07.002 | pmid = 28777933 | pmc = 5544390 }}</ref> In 2022, another likely pathogenic variant (Gln203Arg) was identified in a proband with severe early-onset developmental delay..<ref name="pmid36106513">{{cite journal | vauthors = Tinker RJ, Guess T, Rinker DC, Sheehan JH, Lubarsky D, et al. | title = A novel, likely pathogenic variant in UBTF-related neurodegeneration with brain atrophy is associated with a severe divergent neurodevelopmental phenotype | journal = Molecular Genetics & Genomic Medicine | volume = 10 | issue = 12 | pages = e2054  | date = Dec 2022 | pmid = 36106513 | doi = 10.1002/mgg3.2054 | pmc = 9747545 }}</ref>
== Interactions ==
UBTF has been shown to [[Protein-protein interaction|interact]] with:
* [[Casein kinase 2, alpha 1|CSNK2A1]],<ref name = pmid7651819>{{cite journal | vauthors = Voit R, Kuhn A, Sander EE, Grummt I | title = Activation of mammalian ribosomal gene transcription requires phosphorylation of the nucleolar transcription factor UBF | journal = Nucleic Acids Res. | volume = 23 | issue = 14 | pages = 2593–9  | date = July 1995 | pmid = 7651819 | pmc = 307079 | doi =  10.1093/nar/23.14.2593}}</ref>
* [[Retinoblastoma protein|RB1]],<ref name = pmid11042686>{{cite journal | vauthors = Hannan KM, Hannan RD, Smith SD, Jefferson LS, Lun M, Rothblum LI | title = Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1 | journal = Oncogene | volume = 19 | issue = 43 | pages = 4988–99  | date = October 2000 | pmid = 11042686 | doi = 10.1038/sj.onc.1203875 | doi-access = free }}</ref>
* [[TAF1C]],<ref name = pmid11698641>{{cite journal | vauthors = Voit R, Grummt I | title = Phosphorylation of UBF at serine 388 is required for interaction with RNA polymerase I and activation of rDNA transcription | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 24 | pages = 13631–6  | date = November 2001 | pmid = 11698641 | pmc = 61092 | doi = 10.1073/pnas.231071698 | bibcode = 2001PNAS...9813631V | doi-access = free }}</ref><ref name = pmid10913176>{{cite journal | vauthors = Zhai W, Comai L | title = Repression of RNA polymerase I transcription by the tumor suppressor p53 | journal = Mol. Cell. Biol. | volume = 20 | issue = 16 | pages = 5930–8  | date = August 2000 | pmid = 10913176 | pmc = 86070 | doi =  10.1128/mcb.20.16.5930-5938.2000}}</ref>  and
* [[TAF1]].<ref name = pmid12498690>{{cite journal | vauthors = Lin CY, Tuan J, Scalia P, Bui T, Comai L | title = The cell cycle regulatory factor TAF1 stimulates ribosomal DNA transcription by binding to the activator UBF | journal = Curr. Biol. | volume = 12 | issue = 24 | pages = 2142–6  | date = Dec 2002 | pmid = 12498690 | doi =  10.1016/s0960-9822(02)01389-1| s2cid = 16352280 | doi-access = free }}</ref>
== References ==
{{Reflist}}
== Further reading ==
{{Refbegin|30em}}
* {{cite journal | vauthors = Chan EK, Imai H, Hamel JC, Tan EM | title = Human autoantibody to RNA polymerase I transcription factor hUBF. Molecular identity of nucleolus organizer region autoantigen NOR-90 and ribosomal RNA transcription upstream binding factor | journal = J. Exp. Med. | volume = 174 | issue = 5 | pages = 1239–44 | year = 1991 | pmid = 1940801 | pmc = 2119007 | doi = 10.1084/jem.174.5.1239 }}
* {{cite journal | vauthors = Jantzen HM, Admon A, Bell SP, Tjian R | title = Nucleolar transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins | journal = Nature | volume = 344 | issue = 6269 | pages = 830–6 | year = 1990 | pmid = 2330041 | doi = 10.1038/344830a0 | bibcode = 1990Natur.344..830J | s2cid = 4280039 | doi-access = free }}
* {{cite journal | vauthors = Bell SP, Learned RM, Jantzen HM, Tjian R | title = Functional cooperativity between transcription factors UBF1 and SL1 mediates human ribosomal RNA synthesis | journal = Science | volume = 241 | issue = 4870 | pages = 1192–7 | year = 1988 | pmid = 3413483 | doi = 10.1126/science.3413483 | bibcode = 1988Sci...241.1192B }}
* {{cite journal | vauthors = Voit R, Kuhn A, Sander EE, Grummt I | title = Activation of mammalian ribosomal gene transcription requires phosphorylation of the nucleolar transcription factor UBF | journal = Nucleic Acids Res. | volume = 23 | issue = 14 | pages = 2593–9 | year = 1995 | pmid = 7651819 | pmc = 307079 | doi = 10.1093/nar/23.14.2593 }}
* {{cite journal | vauthors = Hempel WM, Cavanaugh AH, Hannan RD, Taylor L, Rothblum LI | title = The species-specific RNA polymerase I transcription factor SL-1 binds to upstream binding factor | journal = Mol. Cell. Biol. | volume = 16 | issue = 2 | pages = 557–63 | year = 1996 | pmid = 8552083 | pmc = 231034 | doi =  10.1128/MCB.16.2.557}}
* {{cite journal | vauthors = Hanada K, Song CZ, Yamamoto K, Yano K, Maeda Y, Yamaguchi K, Muramatsu M | title = RNA polymerase I associated factor 53 binds to the nucleolar transcription factor UBF and functions in specific rDNA transcription | journal = EMBO J. | volume = 15 | issue = 9 | pages = 2217–26 | year = 1996 | pmid = 8641287 | pmc = 450146 | doi =  10.1002/j.1460-2075.1996.tb00575.x}}
* {{cite journal | vauthors = Pluta AF, Earnshaw WC | title = Specific interaction between human kinetochore protein CENP-C and a nucleolar transcriptional regulator | journal = J. Biol. Chem. | volume = 271 | issue = 31 | pages = 18767–74 | year = 1996 | pmid = 8702533 | doi = 10.1074/jbc.271.31.18767 | doi-access = free }}
* {{cite journal | vauthors = Whitehead CM, Winkfein RJ, Fritzler MJ, Rattner JB | title = ASE-1: a novel protein of the fibrillar centres of the nucleolus and nucleolus organizer region of mitotic chromosomes | journal = Chromosoma | volume = 106 | issue = 8 | pages = 493–502 | year = 1997 | pmid = 9426281 | doi = 10.1007/s004120050271 | s2cid = 10684078 }}
* {{cite journal | vauthors = Voit R, Hoffmann M, Grummt I | title = Phosphorylation by G1-specific cdk-cyclin complexes activates the nucleolar transcription factor UBF | journal = EMBO J. | volume = 18 | issue = 7 | pages = 1891–9 | year = 1999 | pmid = 10202152 | pmc = 1171274 | doi = 10.1093/emboj/18.7.1891 }}
* {{cite journal | vauthors = Liu CJ, Wang H, Lengyel P | title = The interferon-inducible nucleolar p204 protein binds the ribosomal RNA-specific UBF1 transcription factor and inhibits ribosomal RNA transcription | journal = EMBO J. | volume = 18 | issue = 10 | pages = 2845–54 | year = 1999 | pmid = 10329630 | pmc = 1171365 | doi = 10.1093/emboj/18.10.2845 }}
* {{cite journal | vauthors = Hannan KM, Hannan RD, Smith SD, Jefferson LS, Lun M, Rothblum LI | title = Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1 | journal = Oncogene | volume = 19 | issue = 43 | pages = 4988–99 | year = 2000 | pmid = 11042686 | doi = 10.1038/sj.onc.1203875 | doi-access = free }}
* {{cite journal | vauthors = Kalousek I, Krízková P | title = Lymphocyte mitogenic transformation is accompanied by phosphorylation of the nucleolar transcription factor UBF | journal = Cell. Mol. Biol. (Noisy-le-grand) | volume = 46 | issue = 7 | pages = 1163–71 | year = 2000 | pmid = 11075946 }}
* {{cite journal | vauthors = Pelletier G, Stefanovsky VY, Faubladier M, Hirschler-Laszkiewicz I, Savard J, Rothblum LI, Côté J, Moss T | title = Competitive recruitment of CBP and Rb-HDAC regulates UBF acetylation and ribosomal transcription | journal = Mol. Cell | volume = 6 | issue = 5 | pages = 1059–66 | year = 2000 | pmid = 11106745 | doi = 10.1016/S1097-2765(00)00104-0 | doi-access = free }}
* {{cite journal | vauthors = Miller G, Panov KI, Friedrich JK, Trinkle-Mulcahy L, Lamond AI, Zomerdijk JC | title = hRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters | journal = EMBO J. | volume = 20 | issue = 6 | pages = 1373–82 | year = 2001 | pmid = 11250903 | pmc = 145519 | doi = 10.1093/emboj/20.6.1373 }}
* {{cite journal | vauthors = Seither P, Iben S, Thiry M, Grummt I | title = PAF67, a novel protein that is associated with the initiation-competent form of RNA polymerase I | journal = Biol. Chem. | volume = 382 | issue = 8 | pages = 1163–70 | year = 2001 | pmid = 11592397 | doi = 10.1515/BC.2001.146 | s2cid = 28819190 }}
* {{cite journal | vauthors = Voit R, Grummt I | title = Phosphorylation of UBF at serine 388 is required for interaction with RNA polymerase I and activation of rDNA transcription | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 24 | pages = 13631–6 | year = 2001 | pmid = 11698641 | pmc = 61092 | doi = 10.1073/pnas.231071698 | bibcode = 2001PNAS...9813631V | doi-access = free }}
* {{cite journal | vauthors = Stefanovsky VY, Pelletier G, Hannan R, Gagnon-Kugler T, Rothblum LI, Moss T | title = An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF | journal = Mol. Cell | volume = 8 | issue = 5 | pages = 1063–73 | year = 2001 | pmid = 11741541 | doi = 10.1016/S1097-2765(01)00384-7 | doi-access = free }}
* {{cite journal | vauthors = Andersen JS, Lyon CE, Fox AH, Leung AK, Lam YW, Steen H, Mann M, Lamond AI | title = Directed proteomic analysis of the human nucleolus | journal = Curr. Biol. | volume = 12 | issue = 1 | pages = 1–11 | year = 2002 | pmid = 11790298 | doi = 10.1016/S0960-9822(01)00650-9 | s2cid = 14132033 | doi-access = free }}
* {{cite journal | vauthors = Dühr S, Torres-Montaner A, Astola A, García-Cozar FJ, Pendón C, Bolívar J, Valdivia MM | title = Molecular analysis of the 5' region of human ribosomal transcription factor UBF | journal = DNA Seq. | volume = 12 | issue = 4 | pages = 267–72 | year = 2001 | pmid = 11916260 | doi = 10.3109/10425170109025001 | s2cid = 11173681 }}
{{Refend}}
{{PDB Gallery|geneid=7343}}
{{Gene-17-stub}}