UBTF

Upstream binding transcription factor (UBTF), or upstream binding factor (UBF), is a protein that in humans is encoded by the UBTF gene.[5][6]

UBTF
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesUBTF, NOR-90, UBF, UBF-1, UBF1, UBF2, upstream binding transcription factor, RNA polymerase I, CONDBA, upstream binding transcription factor
External IDsOMIM: 600673 MGI: 98512 HomoloGene: 7970 GeneCards: UBTF
Orthologs
SpeciesHumanMouse
Entrez

7343

21429

Ensembl

ENSG00000108312

ENSMUSG00000020923

UniProt

P17480

P25976

RefSeq (mRNA)

NM_001076683
NM_001076684
NM_014233

RefSeq (protein)

NP_001070151
NP_001070152
NP_055048

n/a

Location (UCSC)Chr 17: 44.21 – 44.22 MbChr 11: 102.2 – 102.21 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

In humans, the UBTF gene encodes a 764 amino acid protein and is located on chromosome 17 at position q21.31.[7][8] In mice, UBTF is found on chromosome 11 .

Structure

UBTF contains six high mobility group boxes (HMG-boxes) that allow it to bind to DNA.[9] 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).[9][10]

In humans, alternative splicing can give rise to either the UBTF1 or UBTF2 isoform which are 97 kD and 94 kD in mass, respectively [11] UBTF2 lacks exon 8 of the larger UBTF1 isoform which encodes a portion of HMG Box 2.[12]

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').

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.[13] [supplied by OMIM][6]

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.[14]

UBTF2 has been found to regulate mRNA transcription by RNA Polymerase II.[9]

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.[15] 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.[16]

Additionally, UBTF has been found to facilitate melanoma by promoting GIT1 expression which, in turn, activates MEK1/2-ERK1/2 signaling pathways.[17]

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.[12] 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.[18] In 2022, another likely pathogenic variant (Gln203Arg) was identified in a proband with severe early-onset developmental delay..[19]

Interactions

UBTF has been shown to interact with:

References
  1. GRCh38: Ensembl release 89: ENSG00000108312 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000020923 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Matera AG, Wu W, Imai H, O'Keefe CL, Chan EK (May 1997). "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". Genomics. 41 (1): 135–8. doi:10.1006/geno.1997.4647. PMID 9126496.
  6. "Entrez Gene: UBTF upstream binding transcription factor, RNA polymerase I".
  7. Jones KA, Black DM, Griffiths BL, Solomon E (Dec 1995). "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". Genomics. 30 (3): 602–4. doi:10.1006/geno.1995.1283. PMID 8825649.
  8. Edvardson S, Nicolae CM, Agrawal PB, Mignot C, Payne K, et al. (Aug 2017). "Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood". American Journal of Human Genetics. 101 (2): 267–73. doi:10.1016/j.ajhg.2017.07.002. PMC 5544390. PMID 28777933.
  9. Sanij E, Diesch J, Lesmana A, Poortinga G, Hein N, et al. (Feb 2015). "A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes". Genome Res. 25 (2): 201–12. doi:10.1101/gr.176115.114. PMC 4315294. PMID 25452314.
  10. Schnapp G, Santori F, Carles C, Riva M, Grummt I (Jan 1994). "The HMG box-containing nucleolar transcription factor UBF interacts with a specific subunit of RNA polymerase I". EMBO J. 13 (1): 190–9. doi:10.1002/j.1460-2075.1994.tb06248.x. PMC 394792. PMID 394792.
  11. Bell SP, Learned RM, Jantzen HM, Tjian R (Sep 1988). "Functional cooperativity between transcription factors UBF1 and SL1 mediates human ribosomal RNA synthesis". Science. 241 (4870): 1192–7. Bibcode:1988Sci...241.1192B. doi:10.1126/science.3413483. PMID 3413483.
  12. Toro C, Hori RT, Malicdan MC, Tifft CJ, Goldstein A, et al. (Feb 2018). "A recurrent de novo missense mutation in UBTF causes developmental neuroregression". EMBO J. 27 (4): 691–705. doi:10.1093/hmg/ddx435. PMC 5886272. PMID 29300972.
  13. Jantzen HM, Admon A, Bell SP, Tjian R (Apr 1990). "Nucleolar transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins". Nature. 344 (6269): 830–6. Bibcode:1990Natur.344..830J. doi:10.1038/344830a0. PMID 2330041. S2CID 4280039.
  14. Sanij E, Hannan R (Aug 2009). "The role of UBF in regulating the structure and dynamics of transcriptionally active rDNA chromatin". Epigenetics. 4 (6): 374–82. doi:10.4161/epi.4.6.9449. PMID 19717978. S2CID 30922645.
  15. Diesch J, Bywater MJ, Sanij E, Cameron DP, Schierding W, et al. (Jan 2019). "Changes in long-range rDNA-genomic interactions associate with altered RNA polymerase II gene programs during malignant transformation". Communications Biology. 2: e39(2019). doi:10.1038/s42003-019-0284-y. PMC 6349880. PMID 30701204. S2CID 210151479.
  16. Hamdane N, Herdman C, Mars J, Stefanovsky V, Tremblay MG, Moss T (Sep 2015). "Depletion of the cisplatin targeted HMGB-box factor UBF selectively induces p53-independent apoptotic death in transformed cells". Oncotarget. 6 (29): 27519–27536. doi:10.18632/oncotarget.4823. PMC 4695006. PMID 26317157.
  17. Zhang J, Zhang J, Liu W, Ge R, Gao T, et al. (Oct 2021). "UBTF facilitates melanoma progression via modulating MEK1/2-ERK1/2 signalling pathways by promoting GIT1 transcription". Cancer Cell International. 21 (1): 543(2021). doi:10.1186/s12935-021-02237-8. PMC 8522148. PMID 34663332.
  18. Edvardson S, Nicolae CM, Agrawal PB, Mignot C, Payne K, et al. (Aug 2017). "Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood". American Journal of Human Genetics. 101 (2): 267–73. doi:10.1016/j.ajhg.2017.07.002. PMC 5544390. PMID 28777933.
  19. Tinker RJ, Guess T, Rinker DC, Sheehan JH, Lubarsky D, et al. (Dec 2022). "A novel, likely pathogenic variant in UBTF-related neurodegeneration with brain atrophy is associated with a severe divergent neurodevelopmental phenotype". Molecular Genetics & Genomic Medicine. 10 (12): e2054. doi:10.1002/mgg3.2054. PMC 9747545. PMID 36106513.
  20. Voit R, Kuhn A, Sander EE, Grummt I (July 1995). "Activation of mammalian ribosomal gene transcription requires phosphorylation of the nucleolar transcription factor UBF". Nucleic Acids Res. 23 (14): 2593–9. doi:10.1093/nar/23.14.2593. PMC 307079. PMID 7651819.
  21. Hannan KM, Hannan RD, Smith SD, Jefferson LS, Lun M, Rothblum LI (October 2000). "Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1". Oncogene. 19 (43): 4988–99. doi:10.1038/sj.onc.1203875. PMID 11042686.
  22. Voit R, Grummt I (November 2001). "Phosphorylation of UBF at serine 388 is required for interaction with RNA polymerase I and activation of rDNA transcription". Proc. Natl. Acad. Sci. U.S.A. 98 (24): 13631–6. Bibcode:2001PNAS...9813631V. doi:10.1073/pnas.231071698. PMC 61092. PMID 11698641.
  23. Zhai W, Comai L (August 2000). "Repression of RNA polymerase I transcription by the tumor suppressor p53". Mol. Cell. Biol. 20 (16): 5930–8. doi:10.1128/mcb.20.16.5930-5938.2000. PMC 86070. PMID 10913176.
  24. Lin CY, Tuan J, Scalia P, Bui T, Comai L (Dec 2002). "The cell cycle regulatory factor TAF1 stimulates ribosomal DNA transcription by binding to the activator UBF". Curr. Biol. 12 (24): 2142–6. doi:10.1016/s0960-9822(02)01389-1. PMID 12498690. S2CID 16352280.

Further reading


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