br Discussion br Conflicts of interest
Conflicts of interest
Introduction Ewing\'s sarcoma (EWS) is a bone cancer arising mostly in children. In 1921, EWS was originally described as “diffuse endothelioma of bone” by Dr. James R. Ewing, an American pathologist . In 1992, Ewing sarcoma breakpoint region 1 (EWSR1)/EWS (herein termed EWSR1) gene was identified at chromosomal breakpoint t(11;22)(q24;q12) region from EWS and neuroectodermal tumors as a translocation-generated fusion gene between EWSR1 and FLI1 (Friend leukemia SCH 527123 1) . The EWSR1 gene encodes a RNA/DNA binding protein and involves in various cellular processes. EWSR1 is well-known as a multifunctional protein, which regulates transcription and RNA splicing, indicating that it is involved in diverse cellular processes. N-terminal domains of EWSR1 interacts with the basal transcription factor TFIID and RNA Polymerase II. Moreover, EWSR1 protein is able to modulate gene transcription via interaction with CREB-binding protein (CBP), suggesting that EWSR1 plays a role in basal transcription process [3,4]. Previous studies discovered that EWSR1 regulates the transcriptional activity of HNF4, OCT4 and BRN3A [, , ]. In addition, EWS also serves a role in posttranscriptional mRNA splicing by cooperating with multiple splicing factors . As such, growing body of evidence indicates that EWSR1 concerts various cellular pathways by itself or via multiple interactions with other molecules in a gene-context dependent manner. EWSR1 belongs to a TET (also known as FET) family of proteins, which includes Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS, herein referred as FUS) and TATA-box binding protein Associated Factor 15 (TAF15). EWSR1, FUS and TAF15 are related in both structure and function. TET members are DNA/RNA-binding proteins (RBPs) that mainly contain an N-terminal serine-tyrosine-glycine-glutamine (SYGQ)-rich domain that acts as a transcriptional activation domain, a central RNA recognition domain (RRM) and a C-terminal zinc finger domain involved in RNA and DNA binding, respectively, and multiple Arg‑Gly‑Gly (RRG)-rich regions (RRGs) in the C-terminal that affect RNA binding [, , , ]. The amino acid sequences of these proteins share high homology (~70%), and are evolutionarily conserved from fish to human . TET proteins are expressed in most cell and tissue types, and predominantly reside in the nucleus . In addition, they also have functional similarities. TET members contribute diverse roles in physiological cellular functions, and are involved in the regulation of RNA metabolism. Importantly, recent studies have shown that mutations of TET family genes are closely linked to certain neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) (or termed as frontotemporal lobar degeneration [FTLD]), and essential tremor.
Mutations in TET family genes encoding FUS, EWSR1, and TAF15 have recently been demonstrated to be associated with several neurodegenerative disorders including ALS, FTD/FTLD, and essential tremor that causes involuntary and rhythmic shaking (Fig. 1) [, , , ]. ALS is a neurodegenerative disease that is typically described by the degeneration of lower and upper motor neurons, which leads to a progressive and fatal muscle paralysis (amyotrophic) [, , ]. FTD is caused by the degeneration of neurons in the frontal and temporal lobes, and clinically characterized by progressive disorders of behaviors and personality, as well as language skills. Notably, FTD is ranked as the second most common dementia, just after Alzheimer\'s disease . The findings of TET mutations in ALS and FTD pathology have made a shift in understanding the pathological mechanisms, from RBP aggregation to problem of RNA metabolism . Here, we focus on mutations of EWSR1 and other members of TET family underlying ALS and FTD pathogenesis.