Biology:Non-POU domain-containing octamer-binding protein

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Non-POU domain-containing octamer-binding protein (NonO) is a protein that in humans is encoded by the NONO gene.[1][2][3]

The NonO protein belongs to the Drosophila behaviour/human splicing (DBHS) family of proteins.[4] Proteins in the DHBS family include mammalian SFPQ (splicing factor, proline- and glutamine-rich; a.k.a. PSF), NONO (Non-POU domain-containing octamer-binding protein; a.k.a. p54nrb) and PSPC1 (paraspeckle component 1; a.k.a. PSP1) and invertebrate NONA (Protein no-on-transient A) and Hrp65.[5]

Interactions

NONO has been shown to interact with SFPQ,[6] SPI1[7] and Androgen receptor.[8]

Functions

NONO is involved with many nuclear processes and binds to both DNA and RNA.[9]

As with all proteins of the DBHS familprotein is described as a multifunctional nuclear protein.[10] The NONO protein has been shown to be implicated in many biological functions including, pre-mRNA splicing; activation of transcription; termination of transcription; DNA unwinding and pairing and maintaining correct circadian clock function.[9][11][12][13][14][15]

NONO has been identified to bind with Rasd1 protein, in resulting dimer Rasd1 may act to modulate the function of NONO to down regulate the expression of the CREB genes, NR4A1 and Nr4A2.[16]

NONO binds to SFPQ to form a heterodimer that interacts with the MATR3 protein.[17] The interaction of these three proteins may be part of the process in the nucleus that is responsible for the retention of RNAs that are defective, not yet mature enough to be exported or are designed to be retained in nucleus.[17]

Gene location

NONO protein (Human) is encoded by the NONO gene which is located on the plus strand of the X chromosome.[18]

Role in disease

Melanoma

NONO has been shown to be more strongly expressed in melanoma cell lines and melanoma tissue samples compared to normal human cell lines and normal skin tissue.[19] Studies have found that the knockout of NONO protein from melanoma cell lines results in both reduced proliferation rates of the cancer cells and a significant decrease in the potential migration of the cancer cells.[19]

Breast cancer

Studies into breast cancers have found that the loss or alteration of NONO in conjunction with the loss of the estrogen receptor hERα results in more aggressive breast cancers which show an increase in both tumor size and metastases.[20]

Intellectual disability associated with non-compaction cardiomyopathy

Studies in Humans and mice have identified that NONO null mutations likely lead to the development of a clinically recognizable intellectual disability with cognitive and affective deficits.[21] It was later found that these pathogenic variants were also strongly associated with cardiomyopathy with left ventricular noncompaction and sometimes Ebstein's anomaly.[22][23]

Structure

As with other proteins of the DBHS family, NONO protein functions rarely functions alone and primarily forms homo- and heterodimers with other DBHS proteins to perform its various functions.[24] It is theorised that these dimers may have different functions that are specific to the type of cell that they are found in.[25]

It is speculated that it is the phosphorylation state on NONO that acts to direct the proteins many disparate functions within the nucleus.[9]

Tissue specificity

NONO is found in the nucleus of most mammalian cells and is primarily distributed within the nucleoplasm, it can also be found concentrated within sub-nuclear domains known as paraspeckles.[26]

NONO has also been observed within the brain, localised in the cytoplasm of hippocampal neurons that are associated with RNA transport granules.[27] It is also highly expressed within heart tissue. [23]

Discovery

NONO protein was first discovered in 1993 by researchers at Cold Springs Harbor Laboratory. Due to the protein being originally identified as a RNA-binding protein it was named p54nrb for Nuclear RNA-binding protein, 54 kDa.[4]

References

  1. ↑ "Purification and cDNA cloning of HeLa cell p54nrb, a nuclear protein with two RNA recognition motifs and extensive homology to human splicing factor PSF and Drosophila NONA/BJ6". Nucleic Acids Research 21 (17): 4085–92. August 1993. doi:10.1093/nar/21.17.4085. PMID 8371983. 
  2. ↑ "Loss of expression of a 55 kDa nuclear protein (nmt55) in estrogen receptor-negative human breast cancer". Diagnostic Molecular Pathology 6 (4): 209–21. August 1997. doi:10.1097/00019606-199708000-00005. PMID 9360842. 
  3. ↑ "Entrez Gene: NONO Non-POU domain containing, octamer-binding". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4841. 
  4. ↑ 4.0 4.1 "Purification and cDNA cloning of HeLa cell p54nrb, a nuclear protein with two RNA recognition motifs and extensive homology to human splicing factor PSF and Drosophila NONA/BJ6". Nucleic Acids Research 21 (17): 4085–92. August 1993. doi:10.1093/nar/21.17.4085. PMID 8371983. 
  5. ↑ "Structure of the heterodimer of human NONO and paraspeckle protein component 1 and analysis of its role in subnuclear body formation". Proceedings of the National Academy of Sciences of the United States of America 109 (13): 4846–50. March 2012. doi:10.1073/pnas.1120792109. PMID 22416126. Bibcode: 2012PNAS..109.4846P. 
  6. ↑ "PSF and p54nrb bind a conserved stem in U5 snRNA". RNA 8 (10): 1334–47. October 2002. doi:10.1017/S1355838202022070. PMID 12403470. 
  7. ↑ "The transcription factor Spi-1/PU.1 binds RNA and interferes with the RNA-binding protein p54nrb". The Journal of Biological Chemistry 271 (19): 11177–81. May 1996. doi:10.1074/jbc.271.19.11177. PMID 8626664. 
  8. ↑ "p54nrb acts as a transcriptional coactivator for activation function 1 of the human androgen receptor". Biochemical and Biophysical Research Communications 306 (3): 660–5. July 2003. doi:10.1016/S0006-291X(03)01021-0. PMID 12810069. 
  9. ↑ 9.0 9.1 9.2 "PSF and p54nrb/NonO – multi-functional nuclear proteins". FEBS Lett. 531 (2): 109–14. November 2002. doi:10.1016/S0014-5793(02)03447-6. PMID 12417296. 
  10. ↑ "Structure, Dynamics, and Interaction of p54(nrb)/NonO RRM1 with 5' Splice Site RNA Sequence". Biochemistry 55 (18): 2553–66. May 2016. doi:10.1021/acs.biochem.5b01240. PMID 27064654. 
  11. ↑ "The intracisternal A-particle proximal enhancer-binding protein activates transcription and is identical to the RNA- and DNA-binding protein p54nrb/NonO". Molecular and Cellular Biology 17 (2): 677–86. February 1997. doi:10.1128/mcb.17.2.677. PMID 9001221. 
  12. ↑ "Splicing factors stimulate polyadenylation via USEs at non-canonical 3' end formation signals" (in en). The EMBO Journal 26 (11): 2658–69. June 2007. doi:10.1038/sj.emboj.7601699. PMID 17464285. 
  13. ↑ "The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS" (in en). The Journal of Biological Chemistry 273 (9): 4838–42. February 1998. doi:10.1074/jbc.273.9.4838. PMID 9478924. 
  14. ↑ "p54(nrb) associates with the 5' splice site within large transcription/splicing complexes". The EMBO Journal 23 (8): 1782–91. April 2004. doi:10.1038/sj.emboj.7600187. PMID 15057275. 
  15. ↑ "NONO couples the circadian clock to the cell cycle". Proceedings of the National Academy of Sciences of the United States of America 110 (5): 1592–9. January 2013. doi:10.1073/pnas.1213317110. PMID 23267082. 
  16. ↑ "Rasd1 modulates the coactivator function of NonO in the cyclic AMP pathway". PLOS ONE 6 (9): e24401. 2011-01-01. doi:10.1371/journal.pone.0024401. PMID 21915321. Bibcode: 2011PLoSO...624401O. 
  17. ↑ 17.0 17.1 "The fate of dsRNA in the nucleus: a p54(nrb)-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs". Cell 106 (4): 465–75. August 2001. doi:10.1016/S0092-8674(01)00466-4. PMID 11525732. 
  18. ↑ "NONO - Non-POU domain-containing octamer-binding protein - Homo sapiens (Human) - NONO gene & protein". https://www.uniprot.org/uniprot/Q15233. 
  19. ↑ 19.0 19.1 "p54nrb is a new regulator of progression of malignant melanoma". Carcinogenesis 32 (8): 1176–82. August 2011. doi:10.1093/carcin/bgr103. PMID 21642354. 
  20. ↑ "Immunodetection of nmt55/p54nrb isoforms in human breast cancer". BMC Cancer 1: 15. 2001-01-01. doi:10.1186/1471-2407-1-15. PMID 11710964. 
  21. ↑ "Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects". Nature Neuroscience 18 (12): 1731–6. December 2015. doi:10.1038/nn.4169. PMID 26571461. 
  22. ↑ "Intellectual disability and non-compaction cardiomyopathy with a de novo NONO mutation identified by exome sequencing". European Journal of Human Genetics 24 (11): 1635–1638. November 2016. doi:10.1038/ejhg.2016.72. PMID 27329731. 
  23. ↑ 23.0 23.1 "Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO". Journal of Medical Genetics 54 (1): 47–53. January 2017. doi:10.1136/jmedgenet-2016-104039. PMID 27550220. 
  24. ↑ "P54nrb forms a heterodimer with PSP1 that localizes to paraspeckles in an RNA-dependent manner". Molecular Biology of the Cell 16 (11): 5304–15. November 2005. doi:10.1091/mbc.E05-06-0587. PMID 16148043. 
  25. ↑ "The DBHS proteins SFPQ, NONO and PSPC1: a multipurpose molecular scaffold". Nucleic Acids Research 44 (9): 3989–4004. May 2016. doi:10.1093/nar/gkw271. PMID 27084935. 
  26. ↑ "Paraspeckles" (in en). Cold Spring Harbor Perspectives in Biology 2 (7): a000687. July 2010. doi:10.1101/cshperspect.a000687. PMID 20573717. 
  27. ↑ "Kinesin transports RNA: isolation and characterization of an RNA-transporting granule". Neuron 43 (4): 513–25. August 2004. doi:10.1016/j.neuron.2004.07.022. PMID 15312650. 

Further reading




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