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

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

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. 1 2 3 GRCh38: Ensembl release 89: ENSG00000108312 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 "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. 1 2 3 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. 1 2 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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