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TAF15 (TAF2N or TAFII68) is a nuclear protein known to associate with a distinct subpopulation of transcription factor IID (TFIID), a multi-subunit complex that nucleates the pre-initiation complex on promoters of on protein-coding genes. TAF15 harbors a transcriptional activation domain, a RNA recognition motif and many Arg-Gly-Gly repeats that participate in RNA binding. TAF15 along with FUS and EWS constitutes the FET (FUS/EWS/TAF15) protein family of heterogeneous nuclear ribonucleoproteins (hnRNPs) class of RNA binding proteins that are multifunctional proteins implicated in numerous aspects of RNA processing/functions. TAF15 is a nuclear protein that shuttle between cytoplasm-nucleus and as RNA/ssDNA-binding protein, it play specific roles during transcription initiation at distinct promoters and enter the preinitiation complex together with the RNA polymerase II. TAF15 as well as other FET member genes are frequently translocated in sarcomas and rare hematopoietic as well as epithelial cancers. Moreover, dominant mutations in genes coding for four hnRNPs (TDP-43, FUS/TLS, TAF15, and EWS) are found in familial and sporadic cases of ALS and a chromosomal aberration involving TAF15/TAF2N is found in a form of extraskeletal myxoid chondrosarcomas (EMC).