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UBTF
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases UBTF, NOR-90, UBF, UBF-1, UBF1, UBF2, upstream binding transcription factor, RNA polymerase I, CONDBA, upstream binding transcription factor
External IDs OMIM: 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 Mb Chr 11: 102.2 – 102.21 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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 [ citation needed].

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')[ citation needed].

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. ^ a b c GRCh38: Ensembl release 89: ENSG00000108312 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b "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. ^ a b c 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. ^ a b 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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