SON (gene) explained

SON protein is a protein that in humans is encoded by the SON gene.^{[1] [2]}

SON is the name that has been given to a large Ser/Arg (SR)-related protein, which is a splicing co-factor that contributes to an efficient splicing within cell cycle progression.^[3] It is also known as BASS1 (Bax antagonist selected in saccharomyces 1) or NRE-binding protein (Negative regulatory element-binding protein). The most common gene name of this splicing protein- which is only found in Humans (Homo sapiens)- is SON, but C21orf50, DBP5, KIAA1019 and NREBP can also be used as synonyms.^[4]

The protein encoded by SON gene binds to a specific DNA sequence upstream of the upstream regulatory sequence of the core promoter and second enhancer of human hepatitis B virus (HBV). Through this binding, it represses HBV core promoter activity, transcription of HBV genes, and production of HBV virions. The protein shows sequence similarities with other DNA-binding structural proteins such as gallin, oncoproteins of the MYC family, and the oncoprotein MOS. It may also be involved in protecting cells from apoptosis and in pre-mRNA splicing.^[2] Mutation in SON gene is associated with ZTTK syndrome.^[5]

Structure

The sequence length of the SON protein consists in 2426 aminoacids and its sequence status is totally completed. Its molecular weight is 263,830 daltons (Da) and its domain contains 8 types of repeats which are distributed in 3 regions. This protein is mostly located in nuclear speckles. Its higher expression is seen in leukocyte and heart cells.^{[4] [6]}

Splicing process

SON protein is essential for maintaining the subnuclear organization of the factors that are processed in the nucleus highlighting its direct role in pre-mRNA splicing.^[7]

Splicing is the process through which pre-mRNA is transformed into mRNA. The pre-mRNA which has just been transcribed contains sequences called introns and exons. Introns are non-active nucleotide sequences that must be removed in order for the exons (active sequences) to be joined together forming mRNA. The controlled process of splicing takes place in the spliceosome, a complex that brings together pre-mRNA and a variety of binding proteins. These proteins together with the splicing factors (which are not found in the spliceosome) are in charge of recognizing the 5' ("donor") splice site, 3' ("acceptor") splice site, and branch point sequence within the intron. The SON protein is known to be one of these binding proteins.^[7]

Although there is a lack of knowledge about its exact splicing control in the progression of the cell cycle and it has remained largely unexplored, it’s certain that this splicing-associated protein is necessary for the maintenance of the embryonic stem cells because it influences the splicing of pluripotency regulators.^{[3] [8]}

SON plays an important role in the mRNA processing. Nevertheless, this process is still a little uncertain and this is why in a future it will be interesting to understand how exactly this protein interacts with the spliceosomal complex, its exact molecular function in the context of splicing. Not only the SON protein interferes in the splicing but also makes complex mechanisms such as the RNA post-transcriptional to cooperate with the splicing-mRNA processing.^[9]

Human embryonic stem cells are able to undergo the process of differentiation into specific and relevant cells. To maintain the pluripotency of the embryonic stem cells, transcription factors and epigenetic modifiers play an important role despite the fact that little is known about the regulation of pluripotency throughout the process of splicing. The factor SON is identified as essential for the maintenance of this pluripotency. It is confirmed that SON regulates the splicing process of transcripts (RNAm) that will encode the gens that are going to regulate the pluripotency of the embryonic human cells.^[10]

Function

On the one hand, SON protein is required to maintain the genome stability in order to ensure an efficient RNA processing of affected genes. It also facilitates the interaction of SR proteins with RNA polymerase II and is required for processing of weak constitutive splice sites, having also strong implications in cancer and other human diseases.^{[3] [6]}

On the other side, a deficiency or knockdown of SON protein causes various and severe defects in mitotic division arrangement, chromosome alignment and microtubule dynamics when spindle pole separation takes place.^[3]

But as we could read in the article called “SON protein regulates GATA-2 through transcriptional control of the microRNA 23a-27-24-a clúster”, SON protein has even more functions in the organism. It has been found that these proteins may regulate the hematopoietic cells differentiation. They have a specific job in hematopoietic process, which is based on activating other proteins called GATA. As these ones are finally activated, the cell differentiation starts normally.^[11]

Clinical significance

A recent study suggested that SON may be a novel therapeutic molecular target for pancreatic cancer as the results of a recent study show that this protein is very important as far as proliferation, survival and tumorigenicity of cancer cells are concerned. Specifically, these results revealed that the serine-arginine-rich protein involved in the RNA splicing process, could suppress pancreatic cell tumorigenicity.

The therapeutic implications of the SON gene within virus-host interactions, particularly in the context of viral infections, remain insufficiently defined. Although the SON gene is recognized for its engagement in diverse cellular processes like mRNA splicing, DNA repair, and cell cycle regulation, its precise involvement in the host's response to viral infections and its therapeutic applications remain ambiguous^[12]). Ongoing research is dedicated to unraveling the intricate interactions between host genes, including SON, and HIV-1. This pursuit aims to enhance our comprehension of the dynamics between viruses and hosts, with the potential to unveil novel targets for therapeutic interventions.

RNA Processing and viral replication

SON plays a crucial role in mRNA splicing, a vital process for gene expression. Certain viruses depend on the host's cellular machinery, including the splicing apparatus, for their replication. Disrupting host factors involved in RNA processing could potentially impede viral replication. Aberrations in splicing processes may lead to abnormal protein production and contribute to disease.^[13] Given SON's involvement in RNA processing, it emerges as a promising target for comprehending and treating conditions associated with splicing abnormalities.

Genetic and epigenetic approaches

In the event that SON is identified as a contributor to either promoting or inhibiting viral replication, there is potential for exploring genetic or epigenetic strategies. This could involve manipulating SON expression or activity to influence the viral life cycle.^[14]

Immunomodulation

Host factors also play a role in shaping the immune response to viral infections. If SON is implicated in pathways related to the immune system, modulating its activity could have implications for enhancing the host's capacity to control viral infections.^[15]

Further reading

• Mattioni T, Hume CR, Konigorski S, Hayes P, Osterweil Z, Lee JS . A cDNA clone for a novel nuclear protein with DNA binding activity . Chromosoma . 101 . 10 . 618–624 . October 1992 . 1424986 . 10.1007/BF00360539 . 23195894 .
• Bliskovskiĭ VV, Berdichevskiĭ FB, Tkachenko AV, Belova ME, Chumankov IM . [Coding part of the son gene small transcript contains four areas of complete tandem repeats] . Molekuliarnaia Biologiia . 26 . 4 . 793–806 . 1992 . 1435773 .
• Bliskovskiĭ VV, Kirillov AV, Zakhar'ev VM, Chumankov IM . [The human son gene: the large and small transcripts contains various 5'-terminal sequences] . Molekuliarnaia Biologiia . 26 . 4 . 807–812 . 1992 . 1435774 .
• Tassone F, Cheng S, Gardiner K . Analysis of chromosome 21 yeast artificial chromosome (YAC) clones . American Journal of Human Genetics . 51 . 6 . 1251–1264 . December 1992 . 1463009 . 1682922 .
• Chumakov IM, Berdichevskiĭ FB, Sokolova NV, Reznikov MV, Prasolov VS . [Identification of a protein product of a novel human gene SON and the biological effect upon administering a changed form of this gene into mammalian cells] . Molekuliarnaia Biologiia . 25 . 3 . 731–739 . 1991 . 1944255 .
• Berdichevskiĭ FB, Chumakov IM, Kiselev LL . [Decoding of the primary structure of the son3 region in human genome: identification of a new protein with unusual structure and homology with DNA-binding proteins] . Molekuliarnaia Biologiia . 22 . 3 . 794–801 . 1988 . 3054499 .
• Khan IM, Fisher RA, Johnson KJ, Bailey ME, Siciliano MJ, Kessling AM, Farrer M, Carritt B, Kamalati T, Buluwela L . 6 . The SON gene encodes a conserved DNA binding protein mapping to human chromosome 21 . Annals of Human Genetics . 58 . 1 . 25–34 . January 1994 . 8031013 . 10.1111/j.1469-1809.1994.tb00723.x . 31519119 .
• Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 6 . Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 6 . 3 . 197–205 . June 1999 . 10470851 . 10.1093/dnares/6.3.197 . free .
• Greenhalf W, Lee J, Chaudhuri B . A selection system for human apoptosis inhibitors using yeast . Yeast . 15 . 13 . 1307–1321 . September 1999 . 10509013 . 10.1002/(SICI)1097-0061(19990930)15:13<1307::AID-YEA455>3.0.CO;2-3 . 30982094 . free .
• Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML . 6 . The DNA sequence of human chromosome 21 . Nature . 405 . 6784 . 311–319 . May 2000 . 10830953 . 10.1038/35012518 . free . 2000Natur.405..311H .
• Wynn SL, Fisher RA, Pagel C, Price M, Liu QY, Khan IM, Zammit P, Dadrah K, Mazrani W, Kessling A, Lee JS, Buluwela L . 6 . Organization and conservation of the GART/SON/DONSON locus in mouse and human genomes . Genomics . 68 . 1 . 57–62 . August 2000 . 10950926 . 10.1006/geno.2000.6254 .
• Sun CT, Lo WY, Wang IH, Lo YH, Shiou SR, Lai CK, Ting LP . Transcription repression of human hepatitis B virus genes by negative regulatory element-binding protein/SON . The Journal of Biological Chemistry . 276 . 26 . 24059–24067 . June 2001 . 11306577 . 10.1074/jbc.M101330200 . free .
• Reymond A, Friedli M, Henrichsen CN, Chapot F, Deutsch S, Ucla C, Rossier C, Lyle R, Guipponi M, Antonarakis SE . 6 . From PREDs and open reading frames to cDNA isolation: revisiting the human chromosome 21 transcription map . Genomics . 78 . 1–2 . 46–54 . November 2001 . 11707072 . 10.1006/geno.2001.6640 .
• Yi J, Kloeker S, Jensen CC, Bockholt S, Honda H, Hirai H, Beckerle MC . Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers . The Journal of Biological Chemistry . 277 . 11 . 9580–9589 . March 2002 . 11782456 . 10.1074/jbc.M106922200 . free .
• Casadei R, Strippoli P, D'Addabbo P, Canaider S, Lenzi L, Vitale L, Giannone S, Frabetti F, Facchin F, Carinci P, Zannotti M . 6 . mRNA 5' region sequence incompleteness: a potential source of systematic errors in translation initiation codon assignment in human mRNAs . Gene . 321 . 185–193 . December 2003 . 14637006 . 10.1016/S0378-1119(03)00835-7 . 11586/196824 . free .
• Hillman RT, Green RE, Brenner SE . An unappreciated role for RNA surveillance . Genome Biology . 5 . 2 . R8 . 2005 . 14759258 . 395752 . 10.1186/gb-2004-5-2-r8 . free .
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . 6 . Functional proteomics mapping of a human signaling pathway . Genome Research . 14 . 7 . 1324–1332 . July 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .

Notes and References

1. Cheng S, Lutfalla G, Uze G, Chumakov IM, Gardiner K . GART, SON, IFNAR, and CRF2-4 genes cluster on human chromosome 21 and mouse chromosome 16 . Mammalian Genome . 4 . 6 . 338–342 . Aug 1993 . 8318737 . 10.1007/BF00357094 . 19770065 .
2. Web site: Entrez Gene: SON SON DNA binding protein.
3. Ahn EY, DeKelver RC, Lo MC, Nguyen TA, Matsuura S, Boyapati A, Pandit S, Fu XD, Zhang DE . 6 . SON controls cell-cycle progression by coordinated regulation of RNA splicing . Molecular Cell . 42 . 2 . 185–198 . April 2011 . 21504830 . 3137374 . 10.1016/j.molcel.2011.03.014 .
4. Web site: Protein SON . UniProt Consortium .
5. Web site: OMIM Entry- # 617140 - ZTTK SYNDROME; ZTTKS. omim.org. en-us. 2017-10-27.
6. Web site: Son peptide . MyBioSource.com .
7. Book: Voet D, Voet JG . Biochemistry . 2011 . John Wiley Sons . Hoboken, NJ . 978-0-470-57095-1 .
8. Livyatan I, Meshorer E . SON sheds light on RNA splicing and pluripotency . Nature Cell Biology . 15 . 10 . 1139–1140 . October 2013 . 24084863 . 10.1038/ncb2851 . 12137904 .
9. Furukawa T, Tanji E, Kuboki Y, Hatori T, Yamamoto M, Shimizu K, Shibata N, Shiratori K . 6 . Targeting of MAPK-associated molecules identifies SON as a prime target to attenuate the proliferation and tumorigenicity of pancreatic cancer cells . Molecular Cancer . 11 . 88 . December 2012 . 23227827 . 3576306 . 10.1186/1476-4598-11-88 . free .
10. Lu X, Göke J, Sachs F, Jacques PÉ, Liang H, Feng B, Bourque G, Bubulya PA, Ng HH . 6 . SON connects the splicing-regulatory network with pluripotency in human embryonic stem cells . Nature Cell Biology . 15 . 10 . 1141–1152 . October 2013 . 24013217 . 4097007 . 10.1038/ncb2839 .
11. Ahn EE, Higashi T, Yan M, Matsuura S, Hickey CJ, Lo MC, Shia WJ, DeKelver RC, Zhang DE . 6 . SON protein regulates GATA-2 through transcriptional control of the microRNA 23a~27a~24-2 cluster . The Journal of Biological Chemistry . 288 . 8 . 5381–5388 . February 2013 . 23322776 . 3581430 . 10.1074/jbc.M112.447227 . free .
12. Lu X, Ng HH, Bubulya PA . The role of SON in splicing, development, and disease . Wiley Interdisciplinary Reviews. RNA . 5 . 5 . 637–646 . Sep 2014 . 24789761 . 4138235 . 10.1002/wrna.1235 .
13. Ahn EY, DeKelver RC, Lo MC, Nguyen TA, Matsuura S, Boyapati A, Pandit S, Fu XD, Zhang DE . 6 . SON controls cell-cycle progression by coordinated regulation of RNA splicing . Molecular Cell . 42 . 2 . 185–198 . April 2011 . 21504830 . 3137374 . 10.1016/j.molcel.2011.03.014 .
14. Balakrishnan L, Milavetz B . Epigenetic Regulation of Viral Biological Processes . Viruses . 9 . 11 . 346 . November 2017 . 29149060 . 5707553 . 10.3390/v9110346 . free .
15. Bernard-Raichon L, Cadwell K . Immunomodulation by Enteric Viruses . Annual Review of Virology . 10 . 1 . 477–502 . September 2023 . 37380186 . 10.1146/annurev-virology-111821-112317 . 259286197 . free .