EWSR1, a multifunctional protein, regulates cellular function and aging via genetic and epigenetic pathways

Abstract

Ewing's sarcoma (EWS) is a bone cancer arising predominantly in young children. EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutations of EWSR1 genes are known to be associated with central nervous system disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Otherwise, EWSR1 plays epigenetic roles in gene expression, RNA processing, and cellular signal transduction. Interestingly, EWSR1 controls micro RNA (miRNA) levels via Drosha, leading to autophagy dysfunction and impaired dermal development. Ewsr1 deficiency also leads to premature senescence of blood cells and gamete cells with a high rate of apoptosis due to the abnormal meiosis. Despite these roles of EWSR1 in various cellular functions, the exact mechanisms are not yet understood. In this context, the current review overviews a large body of evidence and discusses on what EWSR1 genetic mutations are associated with brain diseases and on how EWSR1 modulates cellular function via the epigenetic pathway. This will provide a better understanding of bona fide roles of EWSR1 in aging and its association with brain disorders.

Keywords: Autophagy; Brain disorders; EWSR1; Epigenetic function; Genetic mutation; miRNA.

Figure 1:. Scheme representing the domain structure and ALS-associated mutations of TET family (FUS, EWSR1, and TAF15).

TET members have similar domain structure, mainly contain an N-terminal serine-tyrosine-glycine-glutamine (SYGQ)-rich domain that acts as a transcriptional activating domain, a RNA recognition domain (RRM) and a zinc finger domain involved in RNA and DNA binding, respectively, multiple Arg-Gly-Gly (RRG)-rich regions (RRGs) in C-terminal that affect RNA binding, and prolie-tyrosine (PY) region functioning as nuclear localization signal (NLS). Yellow boxes present many kinds of missense-mutations that are found in FUS, EWSR1, and TAF15 gene, respectively.

Figure 2.. EWSR1 is a multifunctional protein and its deficiency impairs tissue-specific functions.

Ewsr1 knockout mice exhibit smaller body size, deregulated brown fat lineage determination, premature cellular senescence, neuronal atrophy and abnormal motor function, XY asynapsis and reduced meiotic recombination, defective in spermato- and oogenesis, impaired epidermal and dermal development, and reduced mitochondria number and activity.

Figure 3.. EWSR1 deficiency influences epithelial cell senescence through an epigenetic modulation of miRNA processing via Drosha.

(i) EWSR1 deficiency increases Drosha expression and certain miRNAs (miR-29b and miR-18b) in the nucleus of epithelial cells. (ii) In turn, miR-29b and miR-18b degrades Col4a1 and CTGF mRNAs in the cytoplasm of epithelial cells. (iii) Consequently, reduction of Col4a1 and CTGF leads to impaired epithelial cell senescence and dermal development.

Figure 4.. EWSR1 plays an epigenetic role in the regulation of autophagy via a posttranscriptional modulation of UVRAG level.

(i) EWSR1 deficiency increases the abnormal processing of pri-miRNAs to pre-mir125a and pre-mir351 by Drosha in the nucleus compartment. (ii) Next, elevated mature miRNA products (miR125a and miR351) degrade Uvrag mRNA in the cytoplasmic compartment. (iii) As a result, impaired UVRAG-dependent autolysosomal pathway leads to autophagy and cellular dysfunction. This figure is adopted from Autophagy (2015) 11 (5):796–811.