Non-POU domain-containing octamer-binding protein explained

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.^{[11] [12] [13] [14] [15]}

NONO has been identified to bind with Rasd1 protein, 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.

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.

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.

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.

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.

Further reading

• Shav-Tal Y, Zipori D . PSF and p54(nrb)/NonO--multi-functional nuclear proteins . FEBS Letters . 531 . 2 . 109–14 . November 2002 . 12417296 . 10.1016/S0014-5793(02)03447-6 . free .
• Zhang WW, Zhang LX, Busch RK, Farrés J, Busch H . Purification and characterization of a DNA-binding heterodimer of 52 and 100 kDa from HeLa cells . The Biochemical Journal . 290 . Pt 1 . 267–72 . February 1993 . 8439294 . 1132410 . 10.1042/bj2900267.
• Hallier M, Tavitian A, Moreau-Gachelin F . 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 . 8626664 . 10.1074/jbc.271.19.11177 . free .
• Peters U, Haberhausen G, Kostrzewa M, Nolte D, Müller U . AFX1 and p54nrb: fine mapping, genomic structure, and exclusion as candidate genes of X-linked dystonia parkinsonism . Human Genetics . 100 . 5–6 . 569–72 . October 1997 . 9341872 . 10.1007/s004390050553 . 35332593 .
• Clark J, Lu YJ, Sidhar SK, Parker C, Gill S, Smedley D, Hamoudi R, Linehan WM, Shipley J, Cooper CS . Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma . Oncogene . 15 . 18 . 2233–9 . October 1997 . 9393982 . 10.1038/sj.onc.1201394 . free .
• Straub T, Grue P, Uhse A, Lisby M, Knudsen BR, Tange TO, Westergaard O, Boege F . The RNA-splicing factor PSF/p54 controls DNA-topoisomerase I activity by a direct interaction . The Journal of Biological Chemistry . 273 . 41 . 26261–4 . October 1998 . 9756848 . 10.1074/jbc.273.41.26261 . free .
• Karhumaa P, Parkkila S, Waheed A, Parkkila AK, Kaunisto K, Tucker PW, Huang CJ, Sly WS, Rajaniemi H . Nuclear NonO/p54(nrb) protein is a nonclassical carbonic anhydrase . The Journal of Biological Chemistry . 275 . 21 . 16044–9 . May 2000 . 10821857 . 10.1074/jbc.275.21.16044 . free .
• Straub T, Knudsen BR, Boege F . PSF/p54(nrb) stimulates "jumping" of DNA topoisomerase I between separate DNA helices . Biochemistry . 39 . 25 . 7552–8 . June 2000 . 10858305 . 10.1021/bi992898e .
• Mathur M, Tucker PW, Samuels HH . PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors . Molecular and Cellular Biology . 21 . 7 . 2298–311 . April 2001 . 11259580 . 86864 . 10.1128/MCB.21.7.2298-2311.2001 .
• Zhang Z, Carmichael GG . 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 . 11525732 . 10.1016/S0092-8674(01)00466-4 . free .
• Pavao M, Huang YH, Hafer LJ, Moreland RB, Traish AM . Immunodetection of nmt55/p54nrb isoforms in human breast cancer . BMC Cancer . 1 . 15 . 2001 . 11710964 . 59838 . 10.1186/1471-2407-1-15 . free .
• Andersen JS, Lyon CE, Fox AH, Leung AK, Lam YW, Steen H, Mann M, Lamond AI . Directed proteomic analysis of the human nucleolus . Current Biology . 12 . 1 . 1–11 . January 2002 . 11790298 . 10.1016/S0960-9822(01)00650-9 . free . 2002CBio...12....1A .
• Sewer MB, Nguyen VQ, Huang CJ, Tucker PW, Kagawa N, Waterman MR . Transcriptional activation of human CYP17 in H295R adrenocortical cells depends on complex formation among p54(nrb)/NonO, protein-associated splicing factor, and SF-1, a complex that also participates in repression of transcription . Endocrinology . 143 . 4 . 1280–90 . April 2002 . 11897684 . 10.1210/endo.143.4.8748 . free .
• Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T . A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein . The Journal of Biological Chemistry . 277 . 43 . 40362–7 . October 2002 . 12171929 . 10.1074/jbc.M206194200 . free .
• Emili A, Shales M, McCracken S, Xie W, Tucker PW, Kobayashi R, Blencowe BJ, Ingles CJ . Splicing and transcription-associated proteins PSF and p54nrb/nonO bind to the RNA polymerase II CTD . RNA . 8 . 9 . 1102–11 . September 2002 . 12358429 . 1370324 . 10.1017/S1355838202025037 .
• Peng R, Dye BT, Pérez I, Barnard DC, Thompson AB, Patton JG . PSF and p54nrb bind a conserved stem in U5 snRNA . RNA . 8 . 10 . 1334–47 . October 2002 . 12403470 . 1370341 . 10.1017/S1355838202022070 .

Notes and References

1. Dong B, Horowitz DS, Kobayashi R, Krainer AR . 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 . 8371983 . 310009 . 10.1093/nar/21.17.4085 .
2. Traish AM, Huang YH, Ashba J, Pronovost M, Pavao M, McAneny DB, Moreland RB . 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 . 9360842 . 10.1097/00019606-199708000-00005 . 1278025 .
3. Web site: Entrez Gene: NONO Non-POU domain containing, octamer-binding.
4. Dong B, Horowitz DS, Kobayashi R, Krainer AR . 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 . 8371983 . 10.1093/nar/21.17.4085 . 310009.
5. Passon DM, Lee M, Rackham O, Stanley WA, Sadowska A, Filipovska A, Fox AH, Bond CS . 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 . 22416126 . 10.1073/pnas.1120792109 . 3324020. 2012PNAS..109.4846P . free .
6. Peng R, Dye BT, Pérez I, Barnard DC, Thompson AB, Patton JG . PSF and p54nrb bind a conserved stem in U5 snRNA . RNA . 8 . 10 . 1334–47 . October 2002 . 12403470 . 1370341 . 10.1017/S1355838202022070 .
7. Hallier M, Tavitian A, Moreau-Gachelin F . 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 . 8626664 . 10.1074/jbc.271.19.11177 . free .
8. Ishitani K, Yoshida T, Kitagawa H, Ohta H, Nozawa S, Kato S . 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 . 12810069 . 10.1016/S0006-291X(03)01021-0 .
9. PSF and p54nrb/NonO – multi-functional nuclear proteins. 10.1016/S0014-5793(02)03447-6 . 12417296. 531. 2 . November 2002. FEBS Lett.. 109–14. Shav-Tal Y, Zipori D. free.
10. Duvignaud JB, Bédard M, Nagata T, Muto Y, Yokoyama S, Gagné SM, Vincent M . Structure, Dynamics, and Interaction of p54(nrb)/NonO RRM1 with 5' Splice Site RNA Sequence . Biochemistry . 55 . 18 . 2553–66 . May 2016 . 27064654 . 10.1021/acs.biochem.5b01240 .
11. Basu A, Dong B, Krainer AR, Howe CC . 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 . 9001221 . 231793 . 10.1128/mcb.17.2.677.
12. Danckwardt S, Kaufmann I, Gentzel M, Foerstner KU, Gantzert AS, Gehring NH, Neu-Yilik G, Bork P, Keller W, Wilm M, Hentze MW, Kulozik AE . Splicing factors stimulate polyadenylation via USEs at non-canonical 3' end formation signals . en . The EMBO Journal . 26 . 11 . 2658–69 . June 2007 . 17464285 . 10.1038/sj.emboj.7601699 . 1888663.
13. Hallier M, Lerga A, Barnache S, Tavitian A, Moreau-Gachelin F . The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS . en . The Journal of Biological Chemistry . 273 . 9 . 4838–42 . February 1998 . 9478924 . 10.1074/jbc.273.9.4838 . free .
14. Kameoka S, Duque P, Konarska MM . p54(nrb) associates with the 5' splice site within large transcription/splicing complexes . The EMBO Journal . 23 . 8 . 1782–91 . April 2004 . 15057275 . 10.1038/sj.emboj.7600187 . 394241 .
15. Kowalska E, Ripperger JA, Hoegger DC, Bruegger P, Buch T, Birchler T, Mueller A, Albrecht U, Contaldo C, Brown SA . 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 . 23267082 . 10.1073/pnas.1213317110 . 3562797. free .
16. Ong SA, Tan JJ, Tew WL, Chen KS . Rasd1 modulates the coactivator function of NonO in the cyclic AMP pathway . PLOS ONE . 6 . 9 . e24401 . 2011-01-01 . 21915321 . 10.1371/journal.pone.0024401 . 3168489. 2011PLoSO...624401O . free .
17. Zhang Z, Carmichael GG . 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 . 11525732 . 10.1016/S0092-8674(01)00466-4. free .
18. Web site: NONO - Non-POU domain-containing octamer-binding protein - Homo sapiens (Human) - NONO gene & protein. www.uniprot.org. 2016-10-14.
19. Schiffner S, Zimara N, Schmid R, Bosserhoff AK . p54nrb is a new regulator of progression of malignant melanoma . Carcinogenesis . 32 . 8 . 1176–82 . August 2011 . 21642354 . 10.1093/carcin/bgr103 . free .
20. Pavao M, Huang YH, Hafer LJ, Moreland RB, Traish AM . Immunodetection of nmt55/p54nrb isoforms in human breast cancer . BMC Cancer . 1 . 15 . 2001-01-01 . 11710964 . 10.1186/1471-2407-1-15 . 59838 . free .
21. Mircsof D, Langouët M, Rio M, Moutton S, Siquier-Pernet K, Bole-Feysot C, Cagnard N, Nitschke P, Gaspar L, Žnidarič M, Alibeu O, Fritz AK, Wolfer DP, Schröter A, Bosshard G, Rudin M, Koester C, Crestani F, Seebeck P, Boddaert N, Prescott K, Hines R, Moss SJ, Fritschy JM, Munnich A, Amiel J, Brown SA, Tyagarajan SK, Colleaux L . Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects . Nature Neuroscience . 18 . 12 . 1731–6 . December 2015 . 26571461 . 5392243 . 10.1038/nn.4169 .
22. Reinstein E, Tzur S, Cohen R, Bormans C, Behar DM . 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 . 27329731 . 5110068 . 10.1038/ejhg.2016.72 .
23. Scott DA, Hernandez-Garcia A, Azamian MS, Jordan VK, Kim BJ, Starkovich M, Zhang J, Wong LJ, Darilek SA, Breman AM, Yang Y, Lupski JR, Jiwani AK, Das B, Lalani SR, Iglesias AD, Rosenfeld JA, Xia F . 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 . 27550220 . 10.1136/jmedgenet-2016-104039 . 206998226 .
24. Fox AH, Bond CS, Lamond AI . 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 . 16148043 . 10.1091/mbc.E05-06-0587 . 1266428.
25. Knott GJ, Bond CS, Fox AH . The DBHS proteins SFPQ, NONO and PSPC1: a multipurpose molecular scaffold . Nucleic Acids Research . 44 . 9 . 3989–4004 . May 2016 . 27084935 . 10.1093/nar/gkw271 . 4872119.
26. Fox AH, Lamond AI . Paraspeckles . en . Cold Spring Harbor Perspectives in Biology . 2 . 7 . a000687 . July 2010 . 20573717 . 10.1101/cshperspect.a000687 . 2890200.
27. Kanai Y, Dohmae N, Hirokawa N . Kinesin transports RNA: isolation and characterization of an RNA-transporting granule . Neuron . 43 . 4 . 513–25 . August 2004 . 15312650 . 10.1016/j.neuron.2004.07.022 . free .