# EWSR1

## Overview
The EWSR1 gene encodes the EWS RNA binding protein 1, a multifunctional RNA/DNA binding protein that belongs to the TET (or FET) family, which also includes FUS and TAF15. This protein is characterized by its involvement in various cellular processes, including transcription regulation, RNA splicing, and microRNA processing. EWSR1 is predominantly located in the nucleus and plays a critical role in RNA metabolism, mitotic progression, and cellular aging. It is particularly notable for its involvement in chromosomal translocations that lead to the formation of oncogenic fusion proteins, which are implicated in several cancers, most notably Ewing sarcoma. Additionally, EWSR1 has been associated with neurodegenerative disorders, highlighting its importance in both oncogenesis and neuronal health (Wang2016EWSR1; Li2022Epigenetic; Lee2019EWSR1).

## Structure
The EWSR1 protein is a multifunctional RNA/DNA binding protein that is part of the TET (or FET) family, which includes FUS and TAF15. It features an N-terminal serine-tyrosine-glycine-glutamine (SYGQ)-rich domain that acts as a transcriptional activation domain, a central RNA recognition motif (RRM), and a C-terminal zinc finger domain involved in RNA and DNA binding (Lee2019EWSR1). The protein also contains multiple arginine-glycine-glycine (RGG) repeats in the C-terminal region, which influence RNA binding (Lee2019EWSR1). 

The N-terminal domains (NTDs) of EWSR1 are disordered and contain S-, Y-, G-, Q-, and T-rich degenerated repeats, which are crucial for forming homo- and heterocomplexes with other FET proteins. This interaction is mediated by a conserved N-terminal motif known as FETBM1, which is essential for the interaction between FET proteins and their oncogenic fusion proteins (Thomsen2013A). The FETBM1 motif includes a high-similarity stretch of 13 amino acids, featuring an acidic residue and potential phosphorylation sites, suggesting regulatory roles (Thomsen2013A). 

EWSR1 is predominantly located in the nucleus and is expressed in most cell and tissue types, playing a role in RNA metabolism and being linked to neurodegenerative disorders (Lee2019EWSR1).

## Function
The EWSR1 gene encodes a multifunctional RNA-binding protein involved in various cellular processes, including transcription regulation, RNA splicing, and microRNA processing. In healthy human cells, EWSR1 is primarily located in the nucleus, where it interacts with transcription factors such as TFIID and RNA Polymerase II, modulating gene transcription through interactions with proteins like CREB-binding protein (CBP) (Lee2019EWSR1). EWSR1 also plays a role in posttranscriptional mRNA splicing by cooperating with multiple splicing factors (Lee2019EWSR1).

EWSR1 is crucial for mitotic progression by influencing microtubule dynamics. It localizes to spindle microtubules during mitosis, interacting with α-tubulin to ensure proper spindle formation and chromosome alignment. This interaction is essential for maintaining genomic stability during cell division (Wang2016EWSR1). EWSR1 regulates microtubule acetylation through histone deacetylase 6 (HDAC6), affecting microtubule stability and function (Wang2016EWSR1).

EWSR1 is also involved in cellular aging and senescence. Its deficiency leads to premature cellular senescence and an aging-like phenotype, highlighting its role in maintaining cellular homeostasis and preventing premature aging (Lee2019EWSR1). The protein's involvement in these processes underscores its importance in healthy cell function and organismal development.

## Clinical Significance
The EWSR1 gene is clinically significant due to its involvement in various cancers, primarily through chromosomal translocations that result in fusion proteins. These fusions are most notably associated with Ewing sarcoma, where the EWSR1 gene fuses with FLI1, forming an oncogenic transcription factor that alters gene expression and contributes to tumorigenesis (Li2022Epigenetic; Flucke2021EWSR1—The). EWSR1 is also implicated in other soft tissue tumors, such as desmoplastic small round cell tumor, clear cell sarcoma, and myxoid liposarcoma, through similar fusion mechanisms (Romeo2009Soft).

In addition to its role in sarcomas, EWSR1 is involved in certain neurodegenerative disorders. Missense mutations in EWSR1 have been linked to central nervous system disorders like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (Lee2019EWSR1). The gene's deficiency in mice has been shown to cause neuronal atrophy and motor dysfunction, highlighting its importance in neuronal health (Lee2019EWSR1).

EWSR1 rearrangements are also found in rare tumors such as intraosseous spindle cell rhabdomyosarcomas with EWSR1-TFCP2 fusion, which pose diagnostic challenges due to their aggressive nature (Panferova2022Case). The diverse clinical implications of EWSR1 fusions underscore the gene's role in oncogenesis and its potential as a therapeutic target (KrystelWhittemore2019Novel).

## Interactions
EWSR1 (EWS RNA binding protein 1) is involved in various interactions with proteins and nucleic acids, playing a significant role in cellular processes. It interacts with the PRDM9 protein during meiotic recombination, influencing the formation of recombination-initiating complexes by linking PRDM9-trimethylated hotspots to the chromosome axis through the cohesin complex containing REC8 (Tian2021EWSR1). EWSR1 also associates with the meiosis-specific cohesin protein pREC8 and synaptonemal complex proteins SYCP3 and SYCP1, facilitating the association between PRDM9 and chromosome axis elements (Tian2021EWSR1).

In transcriptional regulation, EWSR1 interacts with transcription factors such as TFIID and RNA Polymerase II, although its oncogenic fusion variant EWS-FLI-1 does not stably associate with these complexes (Bertolotti1998EWS). EWSR1 also binds with heterogeneous nuclear ribonucleoproteins (hnRNPs) and RNA helicases like p68 and p72, which are involved in RNA-related processes (Pahlich2009Analysis). These interactions occur through its C-terminal RNA-binding domain, which contains RNA-recognition motifs and RGG-boxes (Pahlich2009Analysis).

EWSR1's role extends to mitotic progression, where it interacts with α-tubulin, influencing microtubule acetylation and stability, and potentially competing with HDAC6 for binding to spindle microtubules (Wang2016EWSR1).


## References


[1. (Tian2021EWSR1) Hui Tian, Timothy Billings, and Petko M. Petkov. Ewsr1 affects prdm9-dependent histone 3 methylation and provides a link between recombination hotspots and the chromosome axis protein rec8. Molecular Biology of the Cell, 32(1):1–14, January 2021. URL: http://dx.doi.org/10.1091/mbc.E20-09-0604, doi:10.1091/mbc.e20-09-0604. This article has 16 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1091/mbc.E20-09-0604)

[2. (Pahlich2009Analysis) Steffen Pahlich, Lilian Quero, Bernd Roschitzki, Ruzanna P. Leemann-Zakaryan, and Heinz Gehring. Analysis of ewing sarcoma (ews)-binding proteins: interaction with hnrnp m, u, and rna-helicases p68/72 within protein−rna complexes. Journal of Proteome Research, 8(10):4455–4465, September 2009. URL: http://dx.doi.org/10.1021/pr900235t, doi:10.1021/pr900235t. This article has 31 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/pr900235t)

[3. (Flucke2021EWSR1—The) Uta Flucke, Max M. van Noesel, Vasiliki Siozopoulou, David Creytens, Bastiaan B. J. Tops, Joost M. van Gorp, and Laura S. Hiemcke-Jiwa. Ewsr1—the most common rearranged gene in soft tissue lesions, which also occurs in different bone lesions: an updated review. Diagnostics, 11(6):1093, June 2021. URL: http://dx.doi.org/10.3390/diagnostics11061093, doi:10.3390/diagnostics11061093. This article has 30 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/diagnostics11061093)

[4. (Wang2016EWSR1) Yi-Long Wang, Hui Chen, Yi-Qun Zhan, Rong-Hua Yin, Chang-Yan Li, Chang-Hui Ge, Miao Yu, and Xiao-Ming Yang. Ewsr1 regulates mitosis by dynamically influencing microtubule acetylation. Cell Cycle, 15(16):2202–2215, July 2016. URL: http://dx.doi.org/10.1080/15384101.2016.1200774, doi:10.1080/15384101.2016.1200774. This article has 18 citations and is from a peer-reviewed journal.](https://doi.org/10.1080/15384101.2016.1200774)

[5. (KrystelWhittemore2019Novel) Melissa Krystel-Whittemore, Martin S. Taylor, Miguel Rivera, Jochen K. Lennerz, Long P. Le, Dora Dias-Santagata, Anthony John Iafrate, Vikram Deshpande, Ivan Chebib, Gunnlaugur Petur Nielsen, Chin-Lee Wu, and Valentina Nardi. Novel and established ewsr1 gene fusions and associations identified by next-generation sequencing and fluorescence in-situ hybridization. Human Pathology, 93:65–73, November 2019. URL: http://dx.doi.org/10.1016/j.humpath.2019.08.006, doi:10.1016/j.humpath.2019.08.006. This article has 26 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.humpath.2019.08.006)

[6. (Romeo2009Soft) Salvatore Romeo and Angelo P. Dei Tos. Soft tissue tumors associated with ewsr1 translocation. Virchows Archiv, 456(2):219–234, November 2009. URL: http://dx.doi.org/10.1007/s00428-009-0854-3, doi:10.1007/s00428-009-0854-3. This article has 133 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00428-009-0854-3)

[7. (Li2022Epigenetic) Mingli Li and Chun-Wei Chen. Epigenetic and transcriptional signaling in ewing sarcoma—disease etiology and therapeutic opportunities. Biomedicines, 10(6):1325, June 2022. URL: http://dx.doi.org/10.3390/biomedicines10061325, doi:10.3390/biomedicines10061325. This article has 10 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/biomedicines10061325)

[8. (Panferova2022Case) Agnesa V. Panferova, Kseniya Yu. Sinichenkova, Meriam Abu Jabal, Natalia Yu. Usman, Anastasya S. Sharlai, Vitalii Yu. Roshchin, Dmitry M. Konovalov, and Alexander E. Druy. Case report: ewsr1-tfcp2 in an adolescent represents an extremely rare and aggressive form of intraosseous spindle cell rhabdomyosarcomas. Molecular Case Studies, 8(5):a006209, June 2022. URL: http://dx.doi.org/10.1101/mcs.a006209, doi:10.1101/mcs.a006209. This article has 13 citations.](https://doi.org/10.1101/mcs.a006209)

[9. (Bertolotti1998EWS) Anne Bertolotti, Thomas Melot, Joël Acker, Marc Vigneron, Olivier Delattre, and Laszlo Tora. Ews, but not ews-fli-1, is associated with both tfiid and rna polymerase ii: interactions between two members of the tet family, ews and htafii68, and subunits of tfiid and rna polymerase ii complexes. Molecular and Cellular Biology, 18(3):1489–1497, March 1998. URL: http://dx.doi.org/10.1128/MCB.18.3.1489, doi:10.1128/mcb.18.3.1489. This article has 322 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.18.3.1489)

[10. (Thomsen2013A) Christer Thomsen, Pernilla Grundevik, Per Elias, Anders Ståhlberg, and Pierre Åman. A conserved n‐terminal motif is required for complex formation between fus, ewsr1, taf15 and their oncogenic fusion proteins. The FASEB Journal, 27(12):4965–4974, August 2013. URL: http://dx.doi.org/10.1096/fj.13-234435, doi:10.1096/fj.13-234435. This article has 29 citations.](https://doi.org/10.1096/fj.13-234435)

[11. (Lee2019EWSR1) Junghee Lee, Phuong T. Nguyen, Hyun Soo Shim, Seung Jae Hyeon, Hyeonjoo Im, Mi-Hyun Choi, Sooyoung Chung, Neil W. Kowall, Sean Bong Lee, and Hoon Ryu. Ewsr1, a multifunctional protein, regulates cellular function and aging via genetic and epigenetic pathways. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1865(7):1938–1945, July 2019. URL: http://dx.doi.org/10.1016/j.bbadis.2018.10.042, doi:10.1016/j.bbadis.2018.10.042. This article has 50 citations.](https://doi.org/10.1016/j.bbadis.2018.10.042)