Native proteins generally function in a fully folded tertiary structure conformation in biological cells. In contrast, some native proteins have regions that are not properly structured also called low complexity (LC) domains. For example, RNA-binding FET family proteins, which include: Fused in sarcoma (FUS), Ewing sarcoma (EWS), and TATA-binding protein-associated factor (TAF15) have regions containing low-complexity domains characterized by the abundance of only four amino acids; G, S, Q, and Y. FET family proteins are involved in many biological functions such as regulation of transcription, splicing, and mRNA export. Aberrant chromosomal translocations cause LCs of these FET family proteins fused to DNA binding domains (DBDs) of several other proteins, which results in overexpression of genes that cause some cancers. Previous studies have shown that LCs of FET family proteins activate transcription of genes when fused to DBD, but the mechanism of action of LCs in activating transcription is not known. McKnight et al. attempted to unravel the mechanism of action of LCs in transcription activation. They showed that to activate transcription, the LCs of FET family proteins should polymerize, which helps them bind to the C-terminal domain (CTD) of RNA polymerase II. The authors obtained forty-three Y to S mutants of the LC FUS domain (contains 27 repeats of the [G/S] Y [G/S] triplet sequence) and fused them to the GAL4 DBD. Through luciferase assays, they demonstrated that fused proteins carrying a Y to S mutation activate transcription similar to that of the wild-type (wt) fusion protein, and as the number of Y to S mutations increases, the transcriptional activation capacity of these mutants decreases, with one exceptional mutant called '2...... middle of paper ...... This observation provides evidence for the idea that polymerization of LC domains should precede their binding with CTD of RNA polymerase II. In summary, this study provided useful insights into the mechanism of action of the LC domains of FET proteins and RNA polymerase II. The experimental results of this study convincingly demonstrated that polymerization of the LC domains of FET proteins stimulates their binding to the CTD of RNA polymerase II; subsequent phosphorylation of CTD causes its release from LCs, and this may be necessary for transcriptional elongation by RNA polymerase II. This study is significant for our further understanding of gene expression mechanisms. In the future it will be worth seeing if the same mechanism of action will be followed by other proteins containing LC domains, also it will be useful to look for some anticancer agents that can block the polymerization of defective FET fusion proteins.